Arild Christian Rustan

• Lund, Jenny; Lähteenmäki, Emilia; Eklund, Tiia; Bakke, Hege Gilbø; Thoresen, G. Hege & Pirinen, Eija [Vis alle 9 forfattere av denne artikkelen] (2024). Human HDL subclasses modulate energy metabolism in skeletal muscle cells. Journal of Lipid Research. ISSN 0022-2275. 65(1). doi: 10.1016/j.jlr.2023.100481.
• Krapf, Solveig; Lund, Jenny; Bakke, Hege Gilbø; Nyman, Tuula Anneli; Bartesaghi, Stefano & Peng, Xiao-Rong [Vis alle 9 forfattere av denne artikkelen] (2023). SENP2 knockdown in human adipocytes reduces glucose metabolism and lipid accumulation, while increases lipid oxidation . Metabolism Open. ISSN 2589-9368. 18. doi: 10.1016/j.metop.2023.100234. Fulltekst i vitenarkiv
• Lunde, Ngoc Nguyen; Osoble, Nimo Mukhtar Mohamud; Dalmao-Fernandez, Andrea; Lukacs, Alfreda Serwah; Jafari, Abbas & Singh, Sachin [Vis alle 10 forfattere av denne artikkelen] (2023). Interplay between Cultured Human Osteoblastic and Skeletal Muscle Cells: Effects of Conditioned Media on Glucose and Fatty Acid Metabolism. Biomedicines. 11:2908(11), s. 1–20. doi: 10.3390/biomedicines11112908. Fulltekst i vitenarkiv
• Cho, Bennet S.; Fligor, Scott C.; Fell, Gillian L.; Secor, Jordan D.; Tsikis, Savas T. & Pan, Amy [Vis alle 16 forfattere av denne artikkelen] (2023). A medium-chain fatty acid analogue prevents hepatosteatosis and decreases inflammatory lipid metabolites in a murine model of parenteral nutrition-induced hepatosteatosis. PLOS ONE. ISSN 1932-6203. 18(12). doi: 10.1371/journal.pone.0295244. Fulltekst i vitenarkiv
• Irshad, Zehra; Lund, Jenny; Sillars, Anne; Løvsletten, Nils Gunnar; Gharanei, Seley & Salt, Ian P. [Vis alle 11 forfattere av denne artikkelen] (2023). The roles of DGAT1 and DGAT2 in human myotubes are dependent on donor patho-physiological background. The FASEB Journal. ISSN 0892-6638. 37(11), s. 1–20. doi: 10.1096/fj.202300960RR. Fulltekst i vitenarkiv
• Skagen, Christine; Løvsletten, Nils Gunnar; Asoawe, Lucia; Al-Karbawi, Zeineb; Rustan, Arild Christian & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2023). Functional expression of the thermally activated transient receptor potential channels TRPA1 and TRPM8 in human myotubes. Journal of Thermal Biology. ISSN 0306-4565. 116. doi: 10.1016/j.jtherbio.2023.103623. Fulltekst i vitenarkiv Vis sammendrag

  Transient potential (TRP) ion channels expressed in primary sensory neurons act as the initial detectors of environmental cold and heat, information which controls muscle energy expenditure. We hypothesize that non-neuronal TRPs have direct cellular responses to thermal exposure, also affecting cellular metabolism. In the present study we show expression of TRPA1, TRPM8 and TRPV1 in rat skeletal muscle and human primary myotubes by qPCR. Effects of TRP activity on metabolism in human myotubes were studied using radiolabeled glucose. FURA-2 was used for Ca2+ imaging. TRPA1, TRPM8 and TRPV1 were expressed at low levels in primary human myotubes and in m. gastrocnemius, m. soleus, and m. trapezius from rat. Activation of TRPA1 by ligustilide resulted in an increased glucose uptake and oxidation in human myotubes, whereas activation of TRPM8 by menthol and icilin significantly decreased glucose uptake and oxidation. Activation of heat sensing TRPV1 by capsaicin had no effect on glucose metabolism. Agonist-induced increases in intracellular Ca2+ levels by ligustilide and icilin in human myotubes confirmed a direct activation of TRPA1 and TRPM8, respectively. The mRNA expression of some genes involved in thermogenesis, i.e. peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), uncoupling protein (UCP) 1 and UCP3, were downregulated in human myotubes following TRPA1 activation, while the mRNA expression of TRPM8 and TRPA1 were downregulated following TRPM8 activation by menthol and icilin, respectively. Cold exposure (18 °C) of cultured myotubes followed by a short recovery period had no effect on glucose uptake and oxidation in the basal situation, however when TRPA1 and TRPM8 channels were chemically inhibited a temperature-induced difference in glucose metabolism was found. In conclusion, mRNA of TRPA1, TRPM8 and TRPV1 are expressed in rat skeletal muscle and human skeletal muscle cells. Modulation of TRPA1 and TRPM8 by chemical agents induced changes in Ca2+ levels and glucose metabolism in human skeletal muscle cells, indicating functional receptors.

• Dalmao-Fernandez, Andrea; Aizenshtadt, Aleksandra; Bakke, Hege Gilbø; Krauss, Stefan Johannes Karl; Rustan, Arild Christian & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2023). Development of three-dimensional primary human myospheres as culture model of skeletal muscle cells for metabolic studies. Frontiers in Bioengineering and Biotechnology. ISSN 2296-4185. 11, s. 1–13. doi: 10.3389/fbioe.2023.1130693. Fulltekst i vitenarkiv
• Janovska, Petra; Zouhar, Petr; Bardova, Kristina; Otahal, Jakub; Vrbacky, Marek & Mracek, Tomas [Vis alle 17 forfattere av denne artikkelen] (2023). Impairment of adrenergically-regulated thermogenesis in brown fat of obesity-resistant mice is compensated by non-shivering thermogenesis in skeletal muscle. Molecular Metabolism. ISSN 2212-8778. 69. doi: 10.1016/j.molmet.2023.101683. Fulltekst i vitenarkiv
• Krapf, Solveig; Lund, Jenny; Saqib, Awais Ur Rehman; Bakke, Hege Gilbø; Rustan, Arild Christian & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2022). Pancreatic Cancer Cell-Conditioned, Human-Derived Primary Myotubes Display Increased Leucine Turnover, Increased Lipid Accumulation, and Reduced Glucose Uptake. Metabolites. ISSN 2218-1989. 12(11). doi: 10.3390/metabo12111095. Fulltekst i vitenarkiv
• Katare, Parmeshwar Bajirao; Dalmao Fernandez, Andrea; Mengeste, Abel Mulu; Hamarsland, Håvard; Ellefsen, Stian & Bakke, Hege Gilbø [Vis alle 9 forfattere av denne artikkelen] (2022). Energy metabolism in skeletal muscle cells from donors with different body mass index. Frontiers in Physiology. ISSN 1664-042X. 13. doi: 10.3389/fphys.2022.982842.
• Krajčová, Adéla; Skagen, Christine; Džupa, Valér; Urban, Tomáš; Rustan, Arild Christian & Jiroutková, Kateřina [Vis alle 9 forfattere av denne artikkelen] (2022). Effect of noradrenaline on propofol-induced mitochondrial dysfunction in human skeletal muscle cells. Intensive Care Medicine Experimental. ISSN 2197-425X. 10:47(1), s. 1–14. doi: 10.1186/s40635-022-00474-3. Fulltekst i vitenarkiv
• Schjølberg, Tiril; Asoawe, Lucia; Krapf, Solveig Astrid; Rustan, Arild Christian; Thoresen, G. Hege & Haugen, Fred (2022). Experimental Models for Cold Exposure of Muscle in vitro and in vivo. Bio-protocol. ISSN 2331-8325. 12(13). doi: 10.21769/BioProtoc.4461. Fulltekst i vitenarkiv Vis sammendrag

  Work in cold environments may have a significant impact on occupational health. In these and similar situations, cold exposure localized to the extremities may reduce the temperature of underlying tissues. To investigate the molecular effects of cold exposure in muscle, and since adequate methods were missing, we established two experimental cold exposure models: 1) In vitroexposure to cold (18degreeC) or control temperature (37degreeC) of cultured human skeletal muscle cells (myotubes); and 2) unilateral cold exposure of hind limb skeletal muscle in anesthetized rats (intramuscular temperature 18degreeC), with contralateral control (37degreeC). This methodology enables studies of muscle responses to local cold exposures at the level of gene expression, but also other molecular outcomes.

• Mengeste, Abel Mulu; Nikolic, Natasa; Dalmao Fernandez, Andrea; Feng, Yuan Zeng; Nyman, Tuula Anneli & Kersten, Sander [Vis alle 11 forfattere av denne artikkelen] (2022). Insight Into the Metabolic Adaptations of Electrically Pulse-Stimulated Human Myotubes Using Global Analysis of the Transcriptome and Proteome. Frontiers in Physiology. ISSN 1664-042X. 13. doi: 10.3389/fphys.2022.928195. Vis sammendrag

  Electrical pulse stimulation (EPS) has proven to be a useful tool to interrogate cell-specific responses to muscle contraction. In the present study, we aimed to uncover networks of signaling pathways and regulatory molecules responsible for the metabolic effects of exercise in human skeletal muscle cells exposed to chronic EPS. Differentiated myotubes from young male subjects were exposed to EPS protocol 1 (i.e. 2 ms, 10 V, and 0.1 Hz for 24 h), whereas myotubes from middle-aged women and men were exposed to protocol 2 (i.e. 2 ms, 30 V, and 1 Hz for 48 h). Fuel handling as well as the transcriptome, cellular proteome, and secreted proteins of EPS-treated myotubes from young male subjects were analyzed using a combination of high-throughput RNA sequencing, high-resolution liquid chromatography-tandem mass spectrometry, oxidation assay, and immunoblotting. The data showed that oxidative metabolism was enhanced in EPS-exposed myotubes from young male subjects. Moreover, a total of 81 differentially regulated proteins and 952 differentially expressed genes (DEGs) were observed in these cells after EPS protocol 1. We also found 61 overlapping genes while comparing the DEGs to mRNA expression in myotubes from the middle-aged group exposed to protocol 2, assessed by microarray. Gene ontology (GO) analysis indicated that significantly regulated proteins and genes were enriched in biological processes related to glycolytic pathways, positive regulation of fatty acid oxidation, and oxidative phosphorylation, as well as muscle contraction, autophagy/mitophagy, and oxidative stress. Additionally, proteomic identification of secreted proteins revealed extracellular levels of 137 proteins were changed in myotubes from young male subjects exposed to EPS protocol 1. Selected putative myokines were measured using ELISA or multiplex assay to validate the results. Collectively, our data provides new insight into the transcriptome, proteome and secreted proteins alterations following in vitro exercise and is a valuable resource for understanding the molecular mechanisms and regulatory molecules mediating the beneficial metabolic effects of exercise.

• Mengeste, Abel Mulu; Katare, Parmeshwar Bajirao; Dalmao Fernandez, Andrea; Lund, Jenny; Bakke, Hege Gilbø & Baker, David [Vis alle 11 forfattere av denne artikkelen] (2022). Knockdown of sarcolipin (SLN) impairs substrate utilization in human skeletal muscle cells. Molecular Biology Reports. ISSN 0301-4851. s. 6005–6017. doi: 10.1007/s11033-022-07387-0. Fulltekst i vitenarkiv
• Fraser, David A.; Wang, Xiaoyu; Lund, Jenny; Nikolic, Natasa; Iruarrizaga-Lejarreta, Marta & Skjaeret, Tore [Vis alle 11 forfattere av denne artikkelen] (2022). A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH. Journal of Hepatology. ISSN 0168-8278. 76(4), s. 800–811. doi: 10.1016/j.jhep.2021.12.004.
• Vid, Jan; Mis, Katarina; Nikolic, Natasa; Dolinar, Klemen; Petric, Metka & Bone, Andraz [Vis alle 11 forfattere av denne artikkelen] (2021). Effect of differentiation, de novo innervation, and electrical pulse stimulation on mRNA and protein expression of Na+,K+-ATPase, FXYD1, and FXYD5 in cultured human skeletal muscle cells. PLOS ONE. ISSN 1932-6203. doi: 10.1371/journal.pone.0247377. Fulltekst i vitenarkiv
• Skagen, Christine; Nyman, Tuula Anneli; Xiao-Rong, Peng; O'Mahony, Sven; Kase, Eili Tranheim & Rustan, Arild Christian [Vis alle 7 forfattere av denne artikkelen] (2021). Chronic treatment with terbutaline increases glucose and oleic acid oxidation and protein synthesis in cultured human myotubes. Current Research in Pharmacology and Drug Discovery (CRPHAR). ISSN 2590-2571. 2, s. 1–11. doi: 10.1016/j.crphar.2021.100039.
• Mengeste, Abel Mulu; Lund, Jenny; Katare, Parmeshwar Bajirao; Ghobadi, Roya; Bakke, Hege Gilbø & Lunde, Per Kristian [Vis alle 13 forfattere av denne artikkelen] (2021). The small molecule SERCA activator CDN1163 increases energy metabolism in human skeletal muscle cells. Current Research in Pharmacology and Drug Discovery (CRPHAR). ISSN 2590-2571. 2, s. 1–12. doi: 10.1016/j.crphar.2021.100060.
• Lund, Jenny; Krapf, Solveig Astrid; Sistek, Medina; Bakke, Hege Gilbø; Bartesagi, Stefano & Xiao-Rong, Peng [Vis alle 9 forfattere av denne artikkelen] (2021). SENP2 is vital for optimal insulin signaling and insulin-stimulated glycogen synthesis in human skeletal muscle cells. Current Research in Pharmacology and Drug Discovery (CRPHAR). ISSN 2590-2571. 2, s. 1–10. doi: 10.1016/j.crphar.2021.100061.
• Tingstad, Ragna Husby; Norheim, Frode Amador; Haugen, Fred; Feng, Yuan Zeng; Tunsjø, Hege & Thoresen, G. Hege [Vis alle 9 forfattere av denne artikkelen] (2021). The effect of toll-like receptor ligands on energy metabolism and myokine expression and secretion in cultured human skeletal muscle cells. Scientific Reports. ISSN 2045-2322. 11(1). doi: 10.1038/s41598-021-03730-w. Fulltekst i vitenarkiv Vis sammendrag

  Skeletal muscle plays an important role in glycaemic control and metabolic homeostasis, making it a tissue of interest with respect to type 2 diabetes mellitus. The aim of the present study was to determine if ligands of Toll-like receptors (TLRs) could have an impact on energy metabolism and myokine expression and secretion in cultured human skeletal muscle cells. The myotubes expressed mRNA for TLRs 1–6. TLR3, TLR4, TLR5 and TLR6 ligands (TLRLs) increased glucose metabolism. Furthermore, TLR4L and TLR5L increased oleic acid metabolism. The metabolic effects of TLRLs were not evident until after at least 24 h pre-incubation of the cells and here the metabolic effects were more evident for the metabolism of glucose than oleic acid, with a shift towards effects on oleic acid metabolism after chronic exposure (168 h). However, the stimulatory effect of TLRLs on myokine expression and secretion was detected after only 6 h, where TLR3-6L stimulated secretion of interleukin-6 (IL-6). TLR5L also increased secretion of interleukin-8 (IL-8), while TLR6L also increased secretion of granulocyte–macrophage colony stimulating factor (GM-CSF). Pre-incubation of the myotubes with IL-6 for 24 h increased oleic acid oxidation but had no effect on glucose metabolism. Thus IL-6 did not mimic all the metabolic effects of the TLRLs, implying metabolic effects beyond the actions of this myokine.

• Mengeste, Abel Mulu; Rustan, Arild Christian & Lund, Jenny (2021). Skeletal muscle energy metabolism in obesity. Obesity. ISSN 1930-7381. 29(10), s. 1582–1595. doi: 10.1002/oby.23227.
• Mars, Tomaz; Mis, Katarina; Meznaric, Marija; Mihevc, Sonja Prpar; Vid, Jan & Haugen, Fred [Vis alle 11 forfattere av denne artikkelen] (2020). Innervation and electrical pulse stimulation – in vitro effects on human skeletal muscle cells. Applied Physiology, Nutrition and Metabolism. ISSN 1715-5312. doi: 10.1139/apnm-2019-0575. Vis sammendrag

  Contraction-induced adaptations in skeletal muscles are well characterized in vivo, but the underlying cellular mechanisms are still not completely understood. Cultured human myotubes represent an essential model system for human skeletal muscle which can be modulated ex vivo, but they are quiescent and do not contract unless being stimulated. Stimulation can be achieved by innervation of human myotubes in vitro by co-culturing with embryonic rat spinal cord, or by replacing motor neuron activation by electrical pulse stimulation (EPS). Effects of these two in vitro approaches, innervation and EPS, were characterized with respects to the expression of myosin heavy chains (MyHCs) and metabolism of glucose and oleic acid in cultured human myotubes. Adherent human myotubes were either innervated with rat spinal-cord segments or exposed to EPS. The expression pattern of MyHCs was assessed by qPCR, immunoblotting, and immunofluorescence, while the metabolism of glucose and oleic acid were studied using radiolabeled substrates. Innervation and EPS promoted differentiation towards different fiber types in human myotubes. Expression of the slow MyHC-1 isoform was reduced in innervated myotubes, whereas it remained unaltered in EPS-treated cells. Expression of both fast isoforms (MyHC-2A and MyHC-2X) tended to decrease in EPS-treated cells. Both approaches induced a more oxidative phenotype, reflected in increased CO2 production from both glucose and oleic acid. Novelty: • Innervation and EPS favour differentiation into different fiber types in human myotubes. • Both innervation and EPS promote a metabolically more oxidative phenotype in human myotubes.

• Lund, Jenny & Rustan, Arild (2020). Fatty Acids: Structures and Properties. Encyclopedia of Life Sciences. ISSN 1476-9506. doi: 10.1002/9780470015902.a0029198.
• Aas, Vigdis; Thoresen, G. Hege; Rustan, Arild & Lund, Jenny (2020). Substrate oxidation in primary human skeletal muscle cells is influenced by donor age. Cell and Tissue Research. ISSN 0302-766X. 382, s. 599–608. doi: 10.1007/s00441-020-03275-w. Fulltekst i vitenarkiv
• Løvsletten, Nils Gunnar; Vu, Helene Loang Ngo; Skagen, Christine; Lund, Jenny; Kase, Eili Tranheim & Thoresen, G. Hege [Vis alle 8 forfattere av denne artikkelen] (2020). Treatment of human skeletal muscle cells with inhibitors of diacylglycerol acyltransferases 1 and 2 to explore isozyme-specific roles on lipid metabolism. Scientific Reports. ISSN 2045-2322. 10:238, s. 1–13. doi: 10.1038/s41598-019-57157-5. Fulltekst i vitenarkiv
• Løvsletten, Nils Gunnar; Rustan, Arild; Laurens, Claire; Thoresen, G. Hege; Moro, Cedric & Nikolic, Natasa (2019). Primary defects in lipid handling and resistance to exercise in myotubes from obese donors with and without type 2 diabetes. Applied Physiology, Nutrition and Metabolism. ISSN 1715-5312. doi: 10.1139/apnm-2019-0265.
• Lindquist, Carine; Bjørndal, Bodil; Bakke, Hege Gilbø; Slettom, Grete; Clason, Marie Karoliussen & Rustan, Arild [Vis alle 10 forfattere av denne artikkelen] (2019). A mitochondria-targeted fatty acid analogue influences hepatic glucose metabolism and reduces the plasma insulin/glucose ratio in male Wistar rats. PLOS ONE. ISSN 1932-6203. 14:e0222558(9), s. 1–17. doi: 10.1371/journal.pone.0222558. Fulltekst i vitenarkiv
• Pettersen, Ina Katrine Nitschke; Tusubira, Deusdedit; Ashrafi, Hanan; Dyrstad, Sissel Elisabeth; Hansen, Lena & Liu, Xiaozheng [Vis alle 18 forfattere av denne artikkelen] (2019). Upregulated PDK4 expression is a sensitive marker of increased fatty acid oxidation. Mitochondrion (Amsterdam. Print). ISSN 1567-7249. 49, s. 97–110. doi: 10.1016/j.mito.2019.07.009. Fulltekst i vitenarkiv
• Løvsletten, Nils Gunnar; Bakke, Siril Skaret; Kase, Eili Tranheim; Ouwens, D. Margriet; Thoresen, G. Hege & Rustan, Arild (2018). Increased triacylglycerol - Fatty acid substrate cycling in human skeletal muscle cells exposed to eicosapentaenoic acid. PLOS ONE. ISSN 1932-6203. 13:e0208048(11), s. 1–15. doi: 10.1371/journal.pone.0208048. Fulltekst i vitenarkiv
• Lund, Jenny; Helle, Siw A; Li, Yuchuan; Løvsletten, Nils Gunnar; Stadheim, Hans Kristian & Jensen, Jørgen [Vis alle 9 forfattere av denne artikkelen] (2018). Higher lipid turnover and oxidation in cultured human myotubes from athletic versus sedentary young male subjects. Scientific Reports. ISSN 2045-2322. 8(1). doi: 10.1038/s41598-018-35715-7. Fulltekst i vitenarkiv Vis sammendrag

  In this study we compared fatty acid (FA) metabolism in myotubes established from athletic and sedentary young subjects. Six healthy sedentary (maximal oxygen uptake (VO2max)≤ 46 ml/kg/min) and six healthy athletic (VO2max> 60 ml/kg/min) young men were included. Myoblasts were cultured and diferentiated to myotubes from satellite cells isolated from biopsy of musculus vastus lateralis. FA metabolism was studied in myotubes using [14C]oleic acid. Lipid distribution was assessed by thin layer chromatography, and FA accumulation, lipolysis and re-esterifcation were measured by scintillation proximity assay.Gene and protein expressions were studied. Myotubes from athletic subjects showed lower FA accumulation, lower incorporation of FA into total lipids, triacylglycerol (TAG), diacylglycerol and cholesteryl ester, higherTAG-related lipolysis and re-esterifcation, and higher complete oxidation and incomplete β-oxidation of FA compared to myotubes from sedentary subjects. mRNA expression of the mitochondrial electron transport chain complex III gene UQCRB was higher in cells from athletic compared to sedentary. Myotubes established from athletic subjects have higher lipid turnover and oxidation compared to myotubes from sedentary subjects.Our fndings suggestthat cultured myotubes retain some of the phenotypic traits of their donors.

• Lund, Jenny; Tangen, Daniel S.; Wiig, Håvard; Stadheim, Hans Kristian; Siw, Anette Helle & Birk, Jesper B. [Vis alle 12 forfattere av denne artikkelen] (2017). Glucose metabolism and metabolic flexibility in cultured skeletal muscle cells is related to exercise status in young male subjects. Archives of Physiology and Biochemistry. ISSN 1381-3455. 124(2), s. 119–130. doi: 10.1080/13813455.2017.1369547. Fulltekst i vitenarkiv
• Malecki, Jedrzej Mieczyslaw; Jakobsson, Magnus; Ho, Angela Yeuan Yen; Moen, Anders; Rustan, Arild & Falnes, Pål (2017). Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation. Journal of Biological Chemistry. ISSN 0021-9258. 292(43), s. 17950–17962. doi: 10.1074/jbc.M117.808451. Fulltekst i vitenarkiv
• Feng, Yuan Zeng; Lund, Jenny; Li, Yuchuan; Knabenes, Irlin; Bakke, Siril Skaret & Kase, Eili Tranheim [Vis alle 11 forfattere av denne artikkelen] (2017). Loss of perilipin 2 in cultured myotubes enhances lipolysis and redirects the metabolic energy balance from glucose oxidation towards fatty acid oxidation. Journal of Lipid Research. ISSN 0022-2275. 58(11), s. 2147–2161. doi: 10.1194/jlr.M079764. Fulltekst i vitenarkiv
• Lund, Jenny; Rustan, Arild; Løvsletten, Nils Gunnar; Mudry, Jonathan M.; Langleite, Torgrim Mikal & Feng, Yuan Zeng [Vis alle 19 forfattere av denne artikkelen] (2017). Exercise in vivo marks human myotubes in vitro: Training-induced increase in lipid metabolism. PLOS ONE. ISSN 1932-6203. 12:e0175441(4), s. 1–24. doi: 10.1371/journal.pone.0175441. Fulltekst i vitenarkiv
• Åstrand, Ove Alexander Høgmoen; Viktorsson, Elvar Örn; Kristensen, Aleksander Lim; Ekeberg, Dag; Røberg-Larsen, Hanne & Wilson, Steven Ray Haakon [Vis alle 12 forfattere av denne artikkelen] (2017). Synthesis, in vitro and in vivo biological evaluation of new oxysterols as modulators of the liver X receptors. Journal of Steroid Biochemistry and Molecular Biology. ISSN 0960-0760. 165, s. 323–330. doi: 10.1016/j.jsbmb.2016.07.010. Fulltekst i vitenarkiv
• Lund, Jenny; Stensrud, Camilla; Rajender, Melanie Müller; Bohov, Pavol; Thoresen, G. Hege & Berge, Rolf Kristian [Vis alle 11 forfattere av denne artikkelen] (2016). The molecular structure of thio-ether fatty acids influences PPAR-dependent regulation of lipid metabolism. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 24(6), s. 1191–1203. doi: 10.1016/j.bmc.2016.01.045.
• Kong, Xiang Yi; Feng, Yuan Zeng; Eftestøl, Einar; Kase, Eili Tranheim; Haugum, Hanne & Eskild, Winnie [Vis alle 8 forfattere av denne artikkelen] (2016). Increased glucose utilization and decreased fatty acid metabolism in myotubes from Glmpgt/gt mice. Archives of Physiology and Biochemistry. ISSN 1381-3455. 122(1), s. 36–45. doi: 10.3109/13813455.2015.1120752.
• Coué, Marine; Badin, Pierre-Marie; Vila, Isabelle K.; Laurens, Claire; Louche, Katie & Marquès, Marie-Adeline [Vis alle 15 forfattere av denne artikkelen] (2015). Defective natriuretic peptide receptor signaling in skeletal muscle links obesity to type 2 diabetes. Diabetes. ISSN 0012-1797. 64(12), s. 4033–4045. doi: 10.2337/db15-0305.
• Covington, Jeffrey D.; Myland, Cassandra K.; Rustan, Arild; Ravussin, Eric; Smith, Steven R. & Bajpeyi, Sudip (2015). Effect of serial cell passaging in the retention of fiber type and mitochondrial content in primary human myotubes. Obesity. ISSN 1930-7381. 23(12), s. 2414–2420. doi: 10.1002/oby.21192.
• Covington, Jeffrey D.; Noland, Robert C.; Hebert, R. Caitlin; Masinter, Blaine S.; Smith, Steven R. & Rustan, Arild [Vis alle 8 forfattere av denne artikkelen] (2015). Perilipin 3 differentially regulates skeletal muscle lipid oxidation in active, sedentary, and type 2 diabetic males. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 100(10), s. 3683–3692. doi: 10.1210/JC.2014-4125.
• Kong, Xiang Yi; Kase, Eili Tranheim; Herskedal, Anette; Schjalm, Camilla; Damme, Markus & Nesset, Cecilie Kåsi [Vis alle 9 forfattere av denne artikkelen] (2015). Lack of the lysosomal membrane protein, GLMP, in mice results in metabolic dysregulation in liver. PLOS ONE. ISSN 1932-6203. 10(6). doi: 10.1371/journal.pone.0129402. Fulltekst i vitenarkiv
• Aas, Vigdis; Lund, Jenny; Kase, Eili Tranheim; Feng, Yuan Zeng; Rustan, Arild & Thoresen, G. Hege (2015). Blodglukosesenkende legemidler ved type 2-diabetes. Norsk Farmaceutisk Tidsskrift. ISSN 0029-1935. 123(5), s. 20–24. Fulltekst i vitenarkiv
• Kase, Eili Tranheim; Feng, Yuan Zeng; Badin, Pierre-Marie; Bakke, Siril Skaret; Laurens, C & Coue, M [Vis alle 11 forfattere av denne artikkelen] (2015). Primary defects in lipolysis and insulin action in skeletal muscle cells from type 2 diabetic individuals. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1851(9), s. 1194–1201. doi: 10.1016/j.bbalip.2015.03.005.
• Bakke, Siril Skaret; Feng, Yuan Zeng; Nikolic, Natasa; Kase, Eili Tranheim; Moro, Cedric & Stensrud, Camilla [Vis alle 14 forfattere av denne artikkelen] (2015). Myotubes from Severely Obese Type 2 Diabetic Subjects Accumulate Less Lipids and Show Higher Lipolytic Rate than Myotubes from Severely Obese Non-Diabetic Subjects. PLOS ONE. ISSN 1932-6203. 10(3). doi: 10.1371/journal.pone.0119556. Fulltekst i vitenarkiv
• Feng, Yuan Zeng; Nikolic, Natasa; Bakke, Siril Skaret; Kase, Eili Tranheim; Guderud, Kari & Hjelmesæth, Jøran [Vis alle 9 forfattere av denne artikkelen] (2015). Myotubes from lean and severely obese subjects with and without type 2 diabetes respond differently to an in vitro model of exercise. American Journal of Physiology - Cell Physiology. ISSN 0363-6143. 308(7), s. C548–C556. doi: 10.1152/ajpcell.00314.2014.
• Covington, Jeffrey D.; Galgani, Jose E.; Moro, Cedric; LaGrange, Jamie M; Zhang, Zhengyu & Rustan, Arild [Vis alle 8 forfattere av denne artikkelen] (2014). Skeletal muscle perilipin 3 and coatomer proteins are increased following exercise and are associated with fat oxidation. PLOS ONE. ISSN 1932-6203. 9(3). doi: 10.1371/journal.pone.0091675.
• Bajpeyi, Sudip; Myrland, Cassandra Kim; Covington, Jeffrey D.; Obanda, Diana; Cefalu, W.T. & Smith, Steven R. [Vis alle 8 forfattere av denne artikkelen] (2014). Lipid in skeletal muscle myotubes is associated to the donors' insulin sensitivity and physical activity phenotypes. Obesity. ISSN 1930-7381. 22(2), s. 426–434. doi: 10.1002/oby.20556.
• Åstrand, Ove Alexander Høgmoen; Gikling, Ingveig; Sylte, Ingebrigt; Rustan, Arild; Thoresen, G. Hege & Rongved, Pål [Vis alle 7 forfattere av denne artikkelen] (2014). Development of new LXR modulators that regulate LXR target genes and reduce lipogenesis in human cell models. European Journal of Medicinal Chemistry. ISSN 0223-5234. 74, s. 258–263. doi: 10.1016/j.ejmech.2014.01.003.
• Kong, Xiang Yi; Nesset, Cecilie Kåsi; Damme, Markus; Løberg, Else Marit; Lübke, Torben & Mæhlen, Jan [Vis alle 13 forfattere av denne artikkelen] (2014). Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells. Disease Models and Mechanisms. ISSN 1754-8403. 7(3), s. 351–362. doi: 10.1242/dmm.014050. Fulltekst i vitenarkiv
• Smith, Robert; Solberg, Rigmor; Jacobsen, Linn Løkken; Voreland, Anette Larsen; Rustan, Arild & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2014). Simvastatin inhibits glucose metabolism and legumain activity in human myotubes. PLOS ONE. ISSN 1932-6203. 9(1:85721). doi: 10.1371/journal.pone.0085721.
• Feng, Yuan Zeng; Nikolic, Natasa; Bakke, Siril Skaret; Boekschoten, Mark V.; Kersten, Sander & Kase, Eili Tranheim [Vis alle 8 forfattere av denne artikkelen] (2014). PPARδ activation in human myotubes increases mitochondrial fatty acid oxidative capacity and reduces glucose utilization by a switch in substrate preference. Archives of Physiology and Biochemistry. ISSN 1381-3455. 120(1), s. 12–21. doi: 10.3109/13813455.2013.829105.
• Aas, Vigdis; Bakke, Siril Skaret; Feng, Yuan Zeng; Kase, Eili Tranheim; Jensen, Jørgen & Bajpeyi, Sudip [Vis alle 8 forfattere av denne artikkelen] (2013). Are cultured human myotubes far from home? Cell and Tissue Research. ISSN 0302-766X. 354(3), s. 671–682. doi: 10.1007/s00441-013-1655-1. Fulltekst i vitenarkiv
• Kase, Eili Tranheim; Nikolic, Natasa; Bakke, Siril Skaret; Bogen, Kaja Kamilla; Aas, Vigdis & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2013). Remodelling of oxidative energy metabolism by galactose improves glucose handling and metabolic switching in human skeletal muscle cells. PLOS ONE. ISSN 1932-6203. 8(4). doi: 10.1371/journal.pone.0059972. Fulltekst i vitenarkiv
• Nikolic, Natasa; Rhedin, M; Rustan, Arild; Storlien, Len H.; Thoresen, G. Hege & Strømstedt, Maria (2012). Overexpression of PGC-1α Increases Fatty Acid Oxidative Capacity of Human Skeletal Muscle Cells. Biochemistry Research International. ISSN 2090-2247. 2012. doi: 10.1155/2012/714074.
• Norheim, Frode; Gjelstad, Ingrid Merethe Fange; Hjorth, Marit; Vinknes, Kathrine; Langleite, Torgrim Mikal & Holen, Torgeir [Vis alle 12 forfattere av denne artikkelen] (2012). Molecular nutrition research - the modern way of performing nutritional science. Nutrients. ISSN 2072-6643. 4(12), s. 1898–1944. doi: 10.3390/nu4121898. Vis sammendrag

  In spite of amazing progress in food supply and nutritional science, and a striking increase in life expectancy of approximately 2.5 months per year in many countries during the previous 150 years, modern nutritional research has a great potential of still contributing to improved health for future generations, granted that the revolutions in molecular and systems technologies are applied to nutritional questions. Descriptive and mechanistic studies using state of the art epidemiology, food intake registration, genomics with single nucleotide polymorphisms (SNPs) and epigenomics, transcriptomics, proteomics, metabolomics, advanced biostatistics, imaging, calorimetry, cell biology, challenge tests (meals, exercise, etc.), and integration of all data by systems biology, will provide insight on a much higher level than today in a field we may name molecular nutrition research. To take advantage of all the new technologies scientists should develop international collaboration and gather data in large open access databases like the suggested Nutritional Phenotype database (dbNP). This collaboration will promote standardization of procedures (SOP), and provide a possibility to use collected data in future research projects. The ultimate goals of future nutritional research are to understand the detailed mechanisms of action for how nutrients/foods interact with the body and thereby enhance health and treat diet-related diseases.

• Badin, Pierre-Marie; Loubière, Camille; Coonen, Maarten; Louche, Katie; Tavernier, Geneviève & Bourlier, Virginie [Vis alle 11 forfattere av denne artikkelen] (2012). Regulation of skeletal muscle lipolysis and oxidative metabolism by the co-lipase CGI-58. Journal of Lipid Research. ISSN 0022-2275. 53(5), s. 839–848. doi: 10.1194/jlr.M019182.
• Bakke, Siril Skaret; Moro, Cedric; Nikolic, Natasa; Hessvik, Nina Pettersen; Badin, Pierre-Marie & Lauvhaug, Line [Vis alle 13 forfattere av denne artikkelen] (2012). Palmitic acid follows a different metabolic pathway than oleic acid in human skeletal muscle cells; lower lipolysis rate despite an increased level of adipose triglyceride lipase. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1821(10), s. 1323–1333. doi: 10.1016/j.bbalip.2012.07.001.
• Kase, Eili Tranheim; Nikolic, Natasa; Hessvik, Nina Pettersen; Fjeldheim, Åse-Karine; Jensen, Jørgen & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2012). Dietary supplementation with 22-S-hydroxycholesterol to rats reduces body weight gain and the accumulation of liver triacylglycerol. Lipids. ISSN 0024-4201. 47(5), s. 483–493. doi: 10.1007/s11745-012-3663-4. Vis sammendrag

  This study explores the pharmacokinetics of 22-S-hydroxycholesterol (22SHC) in vivo in rats. We also carried out a metabolic study to explore whether the beneficial effects observed of 22SHC on glucose and lipid metabolism in vitro could be seen in vivo in rats. In the pharmacokinetic study, rats were given 50 mg/kg of [3H]22-S-hydroxycholesterol before absorption, distribution and excretion were monitored. In the metabolic study, the effect of 22SHC (30 mg/kg/day for 3 weeks) in rats on body weight gain [chow and high-fat diet (HFD)], serum lipids triacylglycerol (TAG) content and gene expression in liver and skeletal muscle were examined. Results showed that 22SHC was well absorbed after oral administration and distributed to most organs and mainly excreted in feces. Rats receiving 22SHC gained less body weight than their controls regardless whether the animals received chow diet or HFD. Moreover, we observed that animals receiving HFD had elevated levels of serum TAG while this was not observed for animals on HFD supplemented with 22SHC. The amount of TAG in liver was reduced after 22SHC treatment in animals receiving either chow diet or HFD. Gene expression analysis revealed that two genes (carnitine palmitoyltransferase 2 and uncoupling protein 3) involved in fatty acid oxidation and energy dissipation were increased in liver. Ucp3 expression (both protein and mRNA level) was increased in skeletal muscle, but insulin-stimulated glucose uptake and TAG content were unchanged. In conclusion, 22SHC seems to be an interesting model substance in the search of treatments for disorders involving aberrations in lipid metabolism.

• Nikolic, Natasa; Bakke, Siril Skaret; Kase, Eili Tranheim; Rudberg, Ida; Halle, Ingeborg Flo & Rustan, Arild [Vis alle 8 forfattere av denne artikkelen] (2012). Electrical Pulse Stimulation of Cultured Human Skeletal Muscle Cells as an In Vitro Model of Exercise. PLOS ONE. ISSN 1932-6203. 7(3). doi: 10.1371/journal.pone.0033203. Fulltekst i vitenarkiv
• Hessvik, Nina Pettersen; Bakke, Siril Skaret; Smith, Robert; Ravna, aina westrheim; Sylte, Ingebrigt & Rustan, Arild [Vis alle 8 forfattere av denne artikkelen] (2012). The liver X receptor modulator 22(S)-hydroxycholesterol exerts cell-type specific effects on lipid and glucose metabolism. Journal of Steroid Biochemistry and Molecular Biology. ISSN 0960-0760. 128, s. 154–164. doi: 10.1016/j.jsbmb.2011.10.006.
• Fraser, David; Hessvik, Nina Pettersen; Nikolic, Natasa; Aas, Vigdis; Hanssen, Kristian Folkvord & Bøhn, Siv Kjølsrud [Vis alle 8 forfattere av denne artikkelen] (2012). Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations. Genes & Nutrition. ISSN 1555-8932. doi: 10.1007/s12263-011-0252-8. Fulltekst i vitenarkiv
• Norheim, Frode; Raastad, Truls; Thiede, Bernd; Rustan, Arild; Drevon, Christian A & Haugen, Fred (2011). Proteomic identification of secreted proteins from human skeletal muscle cells and expression in response to strength training. American Journal of Physiology. Endocrinology and Metabolism. ISSN 0193-1849. 301(5), s. E1013–E1021. doi: 10.1152/ajpendo.00326.2011.
• Ciocoiu, Calin C.; Ravna, aina westrheim; Sylte, Ingebrigt; Rustan, Arild & Hansen, Trond Vidar (2011). Synthesis, molecular modeling studies and biological evaluation of fluorine substituted analogs of GW 501516. Bioorganic & Medicinal Chemistry. ISSN 0968-0896. 19, s. 6982–6988. doi: 10.1016/j.bmc.2011.10.020.
• Sparks, LM; Moro, C; Ukropcova, B; Bajpeyi, S; Civitarese, AE & Hulver, MW [Vis alle 9 forfattere av denne artikkelen] (2011). Remodeling Lipid Metabolism and Improving Insulin Responsiveness in Human Primary Myotubes. PLOS ONE. ISSN 1932-6203. 6(7). doi: 10.1371/journal.pone.0021068.
• Nehlin, Jan O.; Just, Marlene; Rustan, Arild & Gaster, Michael (2011). Human myotubes from myoblast cultures undergoing senescence exhibit defects in glucose and lipid metabolism. Biogerontology (Dordrecht). ISSN 1389-5729. 12(4), s. 349–365. doi: 10.1007/s10522-011-9336-5.
• Thoresen, G. Hege; Hessvik, Nina Pettersen; Bakke, Siril Skaret; Aas, Vigdis & Rustan, Arild (2011). Metabolic switching of human skeletal muscle cells in vitro. Prostaglandins, Leukotrienes and Essential Fatty Acids. ISSN 0952-3278. 85(5), s. 227–234. doi: 10.1016/j.plefa.2011.04.017. Fulltekst i vitenarkiv
• Badin, Pierre-Marie; Louche, Katie; Mairal, Aline; Liebisch, Gerhard; Schmitz, Gerd & Rustan, Arild [Vis alle 9 forfattere av denne artikkelen] (2011). Altered Skeletal Muscle Lipase Expression and Activity Contribute to Insulin Resistance in Humans. Diabetes. ISSN 0012-1797. 60(6), s. 1734–1742. doi: 10.2337/db10-1364.
• Aas, Vigdis; Hessvik, Nina Pettersen; Wettergreen, Marianne; Hvammen, Anders Wensaas; Hallen, Stefan & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2011). Chronic hyperglycemia reduces substrate oxidation and impairs metabolic switching of human myotubes. Biochimica et Biophysica Acta - Molecular Basis of Disease. ISSN 0925-4439. 1812(1), s. 94–105. doi: 10.1016/j.bbadis.2010.09.014. Fulltekst i vitenarkiv
• Hessvik, Nina Pettersen; Bakke, Siril Skaret; Fredriksson, K; Boekschoten, MV; Fjørkenstad, Anne & Koster, Gerbrand [Vis alle 11 forfattere av denne artikkelen] (2010). Metabolic switching of human myotubes is improved by n-3 fatty acids. Journal of Lipid Research. ISSN 0022-2275. 51(8), s. 2090–2104. doi: 10.1194/jlr.M003319.
• Hessvik, Nina Pettersen; Boekschoten, MV; Baltzersen, Rose Mari-Ann; Kersten, S; Xu, X & Andersen, H [Vis alle 8 forfattere av denne artikkelen] (2010). LXR beta is the dominant LXR subtype in skeletal muscle regulating lipogenesis and cholesterol efflux. American Journal of Physiology. Endocrinology and Metabolism. ISSN 0193-1849. 298(3), s. E602–E613. doi: 10.1152/ajpendo.00553.2009.
• Corpeleijn, Eva; Hessvik, Nina Pettersen; Bakke, Siril Skaret; Levin, K; Blaak, Ellen E. & Thoresen, G. Hege [Vis alle 8 forfattere av denne artikkelen] (2010). Oxidation of intramyocellular lipids is dependent on mitochondrial function and the availability of extracellular fatty acids. American Journal of Physiology. Endocrinology and Metabolism. ISSN 0193-1849. 299(1), s. E14–E22. doi: 10.1152/ajpendo.00187.2010.
• Rokling-Andersen, Merethe H.; Rustan, Arild; Kaalhus, Olav; Wergedahl, Hege & Drevon, Christian A. (2009). Marine n-3 fatty acids promote size reduction of visceral adipose depots, without altering body weight and composition, in male Wistar rats fed a high-fat diet. British Journal of Nutrition. ISSN 0007-1145. 102(7), s. 995–1006. Vis sammendrag

  We evaluated the effects of partly substituting lard with marine n-3 fatty acids (FA) on body composition and weight, adipose tissue distribution and gene expression in five adipose depots of male Wistar rats fed a high-fat diet. Rats were fed diets including lard (19.5 % lard) or n-3 FA (9.1 % lard and 10.4 % Triomar) for 7 weeks. Feed consumption and weight gain were similar, whereas plasma lipid concentrations were lower in the n-3 FA group. Magnetic resonance imaging revealed smaller visceral (mesenteric, perirenal and epididymal) adipose depots in the n-3 FA-fed animals (35, 44 and 32 % reductions, respectively). n-3 FA feeding increased mRNA expression of cytokines as well as chemokines in several adipose depots. Expression of Adipoq and Pparg was enhanced in the mesenteric adipose depots of the n-3 FA-fed rats, and fasting plasma insulin levels were lowered. Expression of the lipogenic enzymes Acaca and Fasn was increased in the visceral adipose depots, whereas Dgat1 was reduced in the perirenal and epididymal depots. Cpt2 mRNA expression was almost doubled in the mesenteric depot and liver. Carcass analyses showed similar body fat (%) in the two feeding groups, indicating that n-3 FA feeding led to redistribution of fat away from the visceral compartment.

• Wensaas, Andreas J.; Rustan, Arild C.; Just, Marlene; Marlene, Just; Berge, Rolf Kristian & Rolf K, Berge [Vis alle 8 forfattere av denne artikkelen] (2009). Fatty Acid Incubation of Myotubes From Humans With Type 2 Diabetes Leads to Enhanced Release of β-Oxidation Products Because of Impaired Fatty Acid Oxidation. Diabetes. ISSN 0012-1797. 58(3), s. 527–535. doi: 10.2337/db08-1043.
• Løvås, K; Wensaas, AJ; Røst, TH; Rustan, AC; Rokling-Andersen, MH & Skorve, Jon [Vis alle 16 forfattere av denne artikkelen] (2009). Dietary supplementation of tetradecylthioacetic acid increases feed intake but reduces body weight gain and adipose depot sizes in rats fed on high-fat diets. Diabetes, obesity and metabolism. ISSN 1462-8902. 11(11), s. 1034–1049. doi: 10.1111/j.1463-1326.2009.01092.x. Vis sammendrag

  Aim: The pan‐peroxisome proliferator‐activated receptor (PPAR) ligand and fatty acid analogue tetradecylthioacetic acid (TTA) may reduce plasma lipids and enhance hepatic lipid metabolism, as well as reduce adipose tissue sizes in rats fed on high‐fat diets. This study further explores the effects of TTA on weight gain, feed intake and adipose tissue functions in rats that are fed a high‐fat diet for 7 weeks. Methods: The effects on feed intake and body weight during 7 weeks' dietary supplement with TTA (∼200 mg/kg bw) were studied in male Wistar rats fed on a lard‐based diet containing ∼40% energy from fat. Adipose tissue mass, body composition and expression of relevant genes in fat depots and liver were measured at the end of the feeding. Results: Despite higher feed intake during the final 2 weeks of the study, rats fed on TTA gained less body weight than lard‐fed rats and had markedly decreased subcutaneous, epididymal, perirenal and mesenteric adipose depots. The effects of TTA feeding with reduced body weight gain and energy efficiency (weight gain/feed intake) started between day 10 and 13. Body contents of fat, protein and water were reduced after feeding lard plus TTA, with a stronger decrease in fat relative to protein. Plasma lipids, including Non‐Esterified Fatty Acids (NEFA), were significantly reduced, whereas fatty acid β‐oxidation in liver and heart was enhanced in lard plus TTA‐fed rats. Hepatic UCP3 was expressed ectopically both at protein and mRNA level (>1900‐fold), whereas Ucp1 mRNA was increased ∼30‐fold in epididymal and ∼90‐fold in mesenteric fat after lard plus TTA feeding. Conclusion: Our data support the hypothesis that TTA feeding may increase hepatic fatty acid β‐oxidation, and thereby reduce the size of adipose tissues. The functional importance of ectopic hepatic UCP3 is unknown, but might be associated with enhanced energy expenditure and thus the reduced feed efficiency.

• Rokling-Andersen, Merethe; Rokling-Andersen, MH; Rustan, AC; Wensaas, AJ; Kaalhus, O & Wergedahl, Hege [Vis alle 12 forfattere av denne artikkelen] (2009). Marine n-3 fatty acids promote size reduction of visceral adipose depots, without altering body weight and composition, in male Wistar rats fed a high-fat diet. British Journal of Nutrition. ISSN 0007-1145. 102(7), s. 995–1006. doi: 10.1017/S0007114509353210. Vis sammendrag

  We evaluated the effects of partly substituting lard with marine n-3 fatty acids (FA) on body composition and weight, adipose tissue distribution and gene expression in five adipose depots of male Wistar rats fed a high-fat diet. Rats were fed diets including lard (19·5 % lard) or n-3 FA (9·1 % lard and 10·4 % Triomar™) for 7 weeks. Feed consumption and weight gain were similar, whereas plasma lipid concentrations were lower in the n-3 FA group. Magnetic resonance imaging revealed smaller visceral (mesenteric, perirenal and epididymal) adipose depots in the n-3 FA-fed animals (35, 44 and 32 % reductions, respectively). n-3 FA feeding increased mRNA expression of cytokines as well as chemokines in several adipose depots. Expression of Adipoq and Pparg was enhanced in the mesenteric adipose depots of the n-3 FA-fed rats, and fasting plasma insulin levels were lowered. Expression of the lipogenic enzymes Acaca and Fasn was increased in the visceral adipose depots, whereas Dgat1 was reduced in the perirenal and epididymal depots. Cpt2 mRNA expression was almost doubled in the mesenteric depot and liver. Carcass analyses showed similar body fat (%) in the two feeding groups, indicating that n-3 FA feeding led to redistribution of fat away from the visceral compartment.

• Løvås, Kristian; Lovas, K; Røst, Therese Halvorsen; Rost, TH; Skorve, Jon & Ulvik, Rune Johan [Vis alle 12 forfattere av denne artikkelen] (2009). Tetradecylthioacetic acid attenuates dyslipidaemia in male patients with type 2 diabetes mellitus, possibly by dual PPAR-alpha/delta activation and increased mitochondrial fatty acid oxidation. Diabetes, obesity and metabolism. ISSN 1462-8902. 11(4), s. 304–314. doi: 10.1111/j.1463-1326.2008.00958.x.
• Wensaas, Andreas Johansen; Rustan, Arild; Rokling-Andersen, Merethe; Caesar, Robert; Jensen, Jørgen & Kaalhus, O [Vis alle 10 forfattere av denne artikkelen] (2009). Dietary supplementation of tetradecylhioacetic acid increases feed intake but reduces body weight gain and adipose depot sizes in rats fed high fat diets. Diabetes, obesity and metabolism. ISSN 1462-8902. 11(11), s. 1034–1049.
• Kjær, Marte Avranden; Vegusdal, Anne; Gjøen, Tor; Rustan, Arild; Todorcevic, Marijana & Ruyter, Bente (2008). Effect of rapeseed oil and dietary n-3 fatty acids on triacylglycerol synthesis and secretion in Atlantic salmon hepatocytes. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1781(3), s. 112–122. doi: 10.1016/j.bbalip.2007.12.004. Vis sammendrag

  Fish oil (FO) has traditionally been used as the dominating lipid component in fish feed. However, FO is a limited resource and the price varies considerably, which has led to an interest in using alternative oils, such as vegetable oils (VOs), in fish diets. It is far from clear how these VOs affect liver lipid secretion and fish health. The polyunsaturated fatty acids (PUFAs), eicosapentanoic acid (EPA) and docosahexanioc acid (DHA), reduce the secretion of lipoproteins rich in triacylglycerols (TAGs) in Atlantic salmon, as they do in humans. The mechanism by which n-3 fatty acids (FAs) in the diet reduce TAG secretion is not known. We have therefore investigated the effects of rapeseed oil (RO) and n-3 rich diets on the accumulation and secretion of H-3-glycerolipids by salmon hepatocytes. Salmon, of approximately 90 g were fed for 17 weeks on one of four diets supplemented with either 13.5% FO, RO, EPA-enriched oil or DHA-enriched oil until a final average weight of 310 g. Our results show that the dietary FA composition markedly influences the endogenous FA composition and lipid content of the hepatocytes. The intracellular lipid level in hepatocytes from fish fed RO diet and DHA diet were higher, and the expressions of the genes for microsomal transfer protein (MTP) and apolipoprotein A1 (Apo A1) were lower, than those in fish fed the two other diets. Secretion of hepatocyte glycerolipids was lower in fish fed the EPA diet and DHA diet than it was in fish fed the RO diet. Our results indicate that EPA and DHA possess different hypolipidemic properties. Both EPA and DHA inhibit TAG synthesis and secretion, but only EPA induces mitochondrial proliferation and reduce intracellular lipid. Expression of the gene for peroxisome proliferator-activated receptor alpha (PPAR alpha) was higher in the DHA dietary group than it was in the other groups. (C) 2008 Elsevier B.V. All rights reserved.

• Kjær, Marte Avranden; Vegusdal, Anne; Gjøen, Tor; Rustan, Arild; Todorevic, M & Ruyter, B (2008). Effect of rapeseed oil and dietary n-3 fatty acids on triacylglycerol synthesis and secretion in Atlantic salmon hepatocytes. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1781. doi: 10.1016/j.bbalip.2007.12.004.
• Meyer, BJ; Hammervold, T; Rustan, Arild & Howe, PRC (2007). Dose-dependent effects of docosahexaenoic acid supplementation on blood lipids in statin-treated hyperlipidaemic subjects. Lipids. ISSN 0024-4201. 42. doi: 10.1007/s11745-006-3014-4.
• Kase, Eili Tranheim; Thoresen, G. Hege; Westerlund, S; Højlund, K; Rustan, Arild & Gaster, M (2007). Liver X receptor antagonist reduces lipid formation and increases glucose metabolism in myotubes from lean, obese and type 2 diabetic individuals. Diabetologia. ISSN 0012-186X. 50, s. 2171–2180. doi: 10.1007/s00125-007-0760-7.
• Wensaas, Andreas Johansen; Rustan, Arild; Lovstedt, K; Kull, B; Wikstrom, S & Drevon, Christian A [Vis alle 7 forfattere av denne artikkelen] (2007). Cell-based multiwell assays for the detection of substrate accumulation and oxidation. Journal of Lipid Research. ISSN 0022-2275. 48, s. 961–967. doi: 10.1194/jlr.D600047-JLR200.
• Florholmen, Geir; Thoresen, G. Hege; Thoresen, G. Hege; Rustan, Arild Chr.; Jensen, Jørgen & Christensen, Geir [Vis alle 7 forfattere av denne artikkelen] (2006). Leukaemia inhibitory factor stimulates glucose transport in isolated cardiomyocytes and induces insulin resistance after chronic exposure. Diabetologia. ISSN 0012-186X. 49, s. 724–731. doi: 10.1007/s00125-006-0150-6. Vis sammendrag

  Aims/hypothesis: Hypertrophic and failing hearts have increased utilisation of glucose, but also develop insulin resistance and reduced ability to produce ATP. Increased levels of the IL-6-related cytokine leukaemia inhibitory factor (LIF) are found in failing hearts, and we have recently shown that LIF reduces ATP production in isolated cardiomyocytes. In the present study we investigated effects of LIF on glucose metabolism, and how LIF-treated cells respond to insulin stimulation. Methods: Cardiomyocytes were isolated from adult Wistar rats by collagen digestion, maintained in culture for 48 h, and then treated with 1 nmol/l LIF. Results: Acute LIF treatment increased deoxyglucose uptake compared with controls, but no additive effect was observed in cardiomyocytes treated with LIF and insulin. The phosphatidylinositol 3-kinase inhibitor wortmannin did not affect LIF-induced glucose uptake. LIF had no effect on AMP-activated protein kinase phosphorylation. Cardiomyocytes treated with LIF for 48 h did not respond to insulin by increasing deoxyglucose uptake and showed a reduced insulin-mediated uptake of oleic acid and formation of complex lipids compared with control cells. Chronic LIF treatment increased gene expression of the suppressor of cytokine signalling (Socs) 3 and reduced expression of solute carrier family 2, member 4 (Slc2a4, previously known as glucose transporter 4 [Glut4]). In line with these observations, chronic LIF treatment reduced insulin-mediated phosphorylation of both Akt/protein kinase B (PKB) and glycogen synthase kinase (GSK)-3. Conclusions/interpretation: Acute LIF treatment increased glucose uptake in isolated cardiomyocytes by a pathway different from that of insulin. Chronic LIF treatment induced insulin resistance, possibly mediated by altered expression of Socs3 and Slc2a4, and impaired insulin-mediated phosphorylation of GSK-3 and Akt/PKB

• Iversen, Per O.; Sørensen, Dag R.; Tronstad, Karl Johan; Gudbrandsen, Oddrun; Rustan, Arild C. & Berge, Rolf Kristian [Vis alle 7 forfattere av denne artikkelen] (2006). A bioactively modified fatty acid improves survival and impairs metastasis in preclinical models of acute leukemia. Clinical Cancer Research. ISSN 1078-0432. 12(11), s. 3525–3531. doi: 10.1158/1078-0432.CCR-05-2802.
• Kase, Eili Tranheim; Andersen, Bård; Nebb, Hilde Irene; Rustan, Arild & Thoresen, G. Hege (2006). 22-Hydroxycholesterols regulate lipid metabolism differently than T0901317 in human myotubes. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. ISSN 1388-1981. 1761, s. 1515–1522.
• Aas, Vigdis; Rokling-Andersen, Merethe; Kase, Eili Tranheim; Thoresen, G. Hege; Thoresen, G. Hege & Rustan, Arild Chr. (2006). Eicosapentaenoic acid (20 : 5 n-3) increases fatty acid and glucose uptake in cultured human skeletal muscle cells. Journal of Lipid Research. ISSN 0022-2275. 47.
• Aas, Vigdis; Rokling-Andersen, Merethe; Wensaas, Andreas J.; Thoresen, G. Hege; Kase, Eili Tranheim & Rustan, Arild Chr. (2005). Lipid metabolism in human skeletal muscle cells: effects of palmitic acid and chronic hyperglycaemia. Acta Physiologica Scandinavica. ISSN 0001-6772. 183, s. 31–41.
• Aas, Vigdis; Rokling-Andersen, Merete; Wensaas, Andreas Johansen; Thoresen, G. Hege; Kase, Eili Tranheim & Rustan, Arild (2005). Lipid metabolism in human skeletal muscle cells: effects of palmitate and chronic hyperglycaemia. Acta Physiologica Scandinavica. ISSN 0001-6772. 1, s. 31–41.
• Gaster, Michael; Rustan, Arild & Beck-Nielsen, Henning (2005). Differential Utilization of Saturated Palmitate and Unsaturated Oleate - Evidence From Cultured Myotubes. Diabetes. ISSN 0012-1797. 54, s. 648–656. Vis sammendrag

  We recently described a primarily reduced palmitate oxidation in myotubes established from type 2 diabetic subjects, whereas triacylglycerol (TAG) accumulation seemed to be adaptive. However, it is still uncertain whether these changes are similar for saturated and unsaturated fatty acids and whether high concentrations of glucose and/or insulin may change this picture. Studies of palmitic acid and oleic acid metabolism in human myotubes established from control and type 2 diabetic subjects under conditions of acute high concentrations of insulin and/or glucose may solve these questions. Total oleic acid and palmitic acid uptake in myotubes was increased during acute insulin stimulation (P < 0.01) but not under acute, high-glucose concentrations, and no differences were found between the groups. Type 2 diabetic myotubes expressed a reduced palmitic acid oxidation to carbon dioxide (P < 0.04), whereas oleic acid oxidation showed no differences between myotubes from both groups. High glucose concentrations decreased oleic acid oxidation (P < 0.03). Lipid distribution was not different in diabetic and control myotubes when palmitic acid and oleic acid incorporation into cellular lipids was compared. Myotubes that were exposed to palmitic acid showed an increased palmitic acid incorporation into diacylglycerol (DAG) and TAG compared with myotubes that were exposed to oleic acid (P < 0.05) expressing an increased intracellular free fatty acid (FFA) level (P < 0.05). Lipid distribution was not affected by high glucose, whereas insulin increased FFA, DAG, and TAG (P < 0.05). De novo lipid synthesis from glucose in both diabetic and control myotubes was of the same magnitude independent of glucose and insulin concentrations. These results indicate that palmitic acid and oleic acid are utilized in the same pattern in diabetic and control myotubes even though palmitic acid oxidation is primarily reduced in diabetic cells. palmitic acid and oleic acid are handled differently by myotubes: Palmitic acid seems to accumulate as DAG and TAG, whereas oleic acid accumulates as intracellular FFAs. These observations indicate that oleic acid is preferable as fatty acid as it accumulates to a lesser extent as DAG and TAG than palmitic acid. Neither acute hyperglycemia nor de novo lipid synthesis from glucose seems central to the TAG accumulation in obesity or type 2 diabetes.

• Kase, Eili Tranheim; Wensaas, Andreas J.; Aas, Vigdis; Højlund, Kurt; Levin, Klaus & Thoresen, G. Hege [Vis alle 9 forfattere av denne artikkelen] (2005). Skeletal muscle lipid accumulation in type 2 diabetes may involve the liver X receptor pathway. Diabetes. ISSN 0012-1797. 54, s. 1108–1115.
• Solberg, Rigmor; Aas, Vigdis; Thoresen, G. Hege; Kase, Eili Tranheim; Drevon, Christian A. & Rustan, Arild Chr. [Vis alle 7 forfattere av denne artikkelen] (2005). Leptin Expression in Human Primary Skeletal Muscle Cells Is Reduced During Differentiation. Journal of Cellular Biochemistry. ISSN 0730-2312. 96, s. 89–96.
• Solberg, Rigmor; Aas, Vigdis; Thoresen, G. Hege; Kase, Eili Tranheim; Drevon, Christian A & Rustan, Arild [Vis alle 7 forfattere av denne artikkelen] (2005). Leptin expression in human primary skeletal muscle cells is reduced during differentiation. Journal of Cellular Biochemistry. ISSN 0730-2312. 96(1), s. 89–96.
• Kase, Eili Tranheim; Wensaas, Andreas Johansen; Aas, Vigdis; Højlund, K; Levin, K & Thoresen, G. Hege [Vis alle 9 forfattere av denne artikkelen] (2005). Skeletal muscle lipid accumulation in type 2 diabetes may involve the liver X receptor pathway. Diabetes. ISSN 0012-1797. 54, s. 1108–1115.
• Oxley, A; Torstensen, BE; Rustan, Arild & Olsen, RE (2005). Enzyme activities of intestinal triacylglycerol and phosphatidylcholine biosynthesis in Atlantic salmon (Salmo salar L.). Comparative Biochemistry and Physiology - Part B: Biochemistry & Molecular Biology. ISSN 1096-4959. 141.
• Gaster, M; Rustan, Arild; Aas, Vigdis & Beck-Nielsen, H (2004). Reduced lipid oxidation in skeletal muscle from type 2 diabetic subjects may be of genetic origin - Evidence from cultured myotubes. Diabetes. ISSN 0012-1797. 53, s. 542–548. Vis sammendrag

  Insulin resistance in skeletal muscle in vivo is associated with reduced lipid oxidation and linked to lipid accumulation. It is still uncertain whether changes in lipid metabolism represent an adaptive compensation at the cellular level or a direct expression of a genetic trait. Studies of palmitate metabolism in human myotubes established from control and type 2 diabetic (T2D) subjects may solvethis problem, since genetic defects will be preserved and expressed in vitro. Total uptake of palmitic acid (PA) was similar in myotubes established from both groups under basal conditions and conditions of acute insulin stimulation. Myotubes established from T2D subjects expressed a primary reduced PA oxidation to carbon dioxide with a concomitantly increased esterification of PA into phospholipids (PL) compared to control myotubes under basal conditions. Triacylglycerol (TAG) content and the incorporation of PA into diacylglycerol (DAG)and TAG at basal conditions did not vary between the groups. Acute insulin treatment significantly increased palmitate uptake and incorporation of PA into DAG and TAG in myotubes from both study groups, but no difference was found between myotubes from control and T2D subjects. These results indicate that the reduced lipid oxidation in diabetic skeletal muscle in vivo may be of genetic origin, and that TAG metabolism seems not to be primarily affected in diabetic muscles under basal physiological conditions.

• Aas, Vigdis; Kase, Eili Tranheim; Solberg, Rigmor; Jensen, Jørgen & Rustan, Arild (2004). Chronic hyperglycaemia promotes lipogenesis and triacylglycerol accumulation in human skeletal muscle cells. Diabetologia. ISSN 0012-186X. 47, s. 1452–1461.
• Aas, Vigdis; Kase, Eili Tranheim; Solberg, Rigmor; Jensen, Jørgen & Rustan, Arild Chr. (2004). Chronic hyperglycaemia promotes lipogenesis and triacylglycerol accumulation in human skeletal muscle cells. Diabetologia. ISSN 0012-186X. 47(8), s. 1452–1461. Vis sammendrag

  Aims/hypothesis The present study was conducted to evaluate the effect of hyperglycaemia in itself on glucose and lipid metabolism in human skeletal muscle cells. Methods Satellite cells were isolated from biopsy samples from the vastus lateralis muscle and differentiated into multinucleated myotubes in cultures. Metabolism studies were performed using isotopes ([3H]deoxyglucose, [14C]glucose, [14C]oleic acid and [14C]palmitic acid), and mRNA and protein levels were analysed by real-time RT-PCR and western blotting respectively. Results Exposure of myotubes to 20 mmol/l glucose for 4 days reduced insulin-stimulated glucose uptake and glycogen synthesis to 57±5% (p<0.0001) and 56±5% (p<0.0001) of normoglycaemic (5.5 mmol/l glucose) controls respectively. Basal glucose uptake and glycogen synthesis were both reduced, whereas glucose oxidation was unaltered. Total cell content of glycogen and expression of GLUT1 and GLUT4 mRNA were not affected. There was a significant increase in the incorporation of glucose into cellular NEFA (88±17% increase, p=0.006), triacylglycerol (44±21% increase, p=0.04) and cholesterol ester (89±36% increase, p=0.02) in hyperglycaemic myotubes compared with controls. Diacylglycerol tended to be increased though not significantly, and phospholipid formation were unchanged. Relative to controls, total cell content of triacylglycerol was increased by 25±7% (p=0.02) and acyl-CoA:1,2-diacylglycerol acyltransferase 1 activity was increased by 34±4% (p=0.004), whereas acyl-CoA:1,2-diacylglycerol acyltransferase 1 mRNA expression was unchanged. Total cellular uptake of palmitic acid was reduced by 18±3% (p=0.006) in hyperglycaemic cells compared with controls, while uptake of oleic acid was unchanged. Oxidation of palmitic acid or oleic acid was not affected by hyperglycaemia. Conclusions/interpretation Chronic hyperglycaemia increased triacylglycerol accumulation and the incorporation of carbohydrate into triacylglycerol (i.e. de novo lipogenesis) concomitantly with a reduced insulin-stimulated glucose uptake and glycogen synthesis. Enhanced acyl-CoA:1,2-diacylglycerol acyltransferase 1 activity supported the increased triacylglycerol synthesis during hyperglycaemia.

• Florholmen, Geir; Aas, Vigdis; Rustan, Arild Chr.; Lunde, Per Kristian; Straumann, Nadine & Eid, Hilde [Vis alle 10 forfattere av denne artikkelen] (2004). Leukemia inhibitory factor reduces contractile function and induces alterations in energy metabolism in isolated cardiomycytes. Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 37, s. 1183–1193.
• Rustan, Arild (2003). Arachidonic acid-dependent inhibition of adipocyte differentiation requires PKA activity and is associated with sustained expression of cyclooxygenases. Journal of Lipid Research. ISSN 0022-2275. 44, s. 2320–2330. Vis sammendrag

  Arachidonic acid has been shown to inhibit adipocyte differentiation of 3T3-L1 cells via a prostaglandin synthesis-dependent pathway. Accordingly, inclusion of non-selective cyclooxygenase (COX)-inhibitors was shown to rescue adipocyte differentiation in the presence of arachidonic acid. Here we show that arachidonic acid-mediated inhibition of adipocyte differentiation requires the presence of a cAMP-elevating agent in the adipogenic cocktail during the first two days of the differentiation process. Furthermore, suppression of the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) or protein kinase A (PKA) by the selective inhibitors U0126 and H-89, respectively, restored the ability of arachidonic acid-treated cells to undergo differentiation. 3T3-L1 preadipocytes express both COX-isoforms. We show that expression of COX-2 is transiently induced during the first hours of the differentiation program and then declines to become almost undetectable in fully differentiated adipocytes. COX-1 expression declines gradually as differentiation progresses, but expression is still detectable in mature adipocytes. Treatment with arachidonic acid led to a sustained expression of COX-1 and COX-2. Omission of a cAMP-elevating agent or addition of U0126 or H-89 prevents sustained expression of COX-2. Surprisingly, selective inhibition of either COX-1 or COX-2 rescued adipocyte differentiation in the presence of arachidonic acid as effectively as the non-selective COX-inhibitor indomethacin. When cells were induced to differentiate in the presence of arachidonic acid de novo fatty acid synthesis, diacylglycerol acyltransferase (DGAT) activity and triacylglycerol accumulation were inhibited. Indomethacin restored DGAT activity and triacylglycerol accumulation without restoring de novo fatty acid synthesis, and under these conditions enhanced incorporation of arachidonic acid into cellular triacylglycerols was observed.

• Rustan, Arild & Drevon, Christian A (2003). The hypotriglyceridemic effect of dietary n-3 FA is associated with increased beta-oxidation and reduced leptin expression. Lipids. ISSN 0024-4201. 38, s. 1023–1029. Vis sammendrag

  To study the mechanisms responsible for the hypotriglyceridemic effect of marine oils, we monitored the effects of high dietary intake of n-3 PUFA on hepatic and muscular beta-oxidation, plasma leptin concentration, leptin receptor gene expression, and in vivo insulin action. Two groups of male Wistar rats were fed either a high-fat diet [28% (w/w) of saturated fat] or a high-fat diet containing 10% n-3 PUFA and 18% saturated fat for 3 wk. The hypotriglyceridemic effect of n-3 PUFA was accompanied by increased hepatic oxidation of palmitoyl-CoA (125%, P < 0.005) and palmitoyl-L-carnitine (480%, P < 0.005). These findings were corroborated by raised carnitine palmitoyltransferase-2 activity (154%, P < 0.001) and mRNA levels (91%, P < 0.01) as well as by simultaneous elevation of hepatic peroxisomal acyl-CoA oxidase activity (144%, P < 0.01) and mRNA content (82%, P < 0.05). In contrast, hepatic carnitine palmitoyltransferase-1 activity remained unchanged despite a twofold increased mRNA level after n-3 PUFA feeding. Skeletal muscle FA oxidation was less affected by dietary n-3 PUFA, and the stimulatory effect was found only in peroxisomes. Dietary intake of n-3 PUFA was followed by increased acyl-CoA oxidase activity (48%, P < 0.05) and mRNA level (83%, P < 0.05) in skeletal muscle. The increased FA oxidation after n-3 PUFA supplementation of the high-fat diet was accompanied by lower plasma leptin concentration (-38%, P < 0.05) and leptin mRNA expression (-66%, P < 0.05) in retroperitoneal adipose tissue, and elevated hepatic mRNA level for the leptin receptor Ob-Ra (140%, P < 0.05). Supplementation of the high-fat diet with n-3 PUFA enhanced in vivo insulin sensitivity, as shown by normalization of the glucose infusion rate during euglycemic hyperinsulinemic clamp. Our results indicate that the hypotriglyceridemic effect of dietary n-3 PUFA is associated with stimulation of FA oxidation in the liver and to a smaller extent in skeletal muscle. This may ameliorate dyslipidemia, tissue lipid accumulation, and insulin action, in spite of decreased plasma leptin level and leptin mRNA in adipose tissue.

• Ukropec, Jozef; Reseland, Janne Elin; Rustan, Arild & Drevon, Christian A (2003). The hyperleptinemic effect of dietary fish oil is associated with increased &#61538;-oxidation and reduced leptin expression. Lipids. ISSN 0024-4201. 38(10), s. 1023–1029.
• Petersen, Rasmus K.; Petersen, RK; Jørgensen, Claus; Jorgensen, C; Rustan, Arild C. & Frøyland, Livar [Vis alle 16 forfattere av denne artikkelen] (2003). Arachidonic acid-dependent inhibition of adipocyte differentiation requires PKA activity and is associated with sustained expression of cyclooxygenases. Journal of Lipid Research. ISSN 0022-2275. 44, s. 2320–2330.
• Gedde-Dahl, Ane; Kulseth, M. A.; Ranheim, Trine; Drevon, Christian A & Rustan, Arild (2002). Reduced secretion of triacylglycerol in CaCo-2 cells transfected with intestinal fatty acid-binding protein. Lipids. ISSN 0024-4201. 37, s. 61–68. Vis sammendrag

  The fatty acid-binding proteins are hypothesized to be involved in cellular fatty acids transport and trafficking. We have established CaCo-2 cells stably transfected with intestinal fatty acid-binding protein (I-FABP), and have examined how the expression of this protein may influence fatty acid metabolism. I-FABP expression was detectable in I-FABP-transfected cells, whereas parent CaCo-2 cells as well as mock-transfected cells failed to express detectable levels of I-FABP mRNA or protein at any stage of differentiation. For studies of lipid metabolism, cells were incubated with [14C]oleic acid in taurocholate micelles containing monoolein, and distribution of labeled fatty acid in cellular and secreted lipids was examined. In one transfected cell clone, expressing the highest level of I-FABP, labeled cellular triacylglycerol was increased approximately two-fold as compared to control cells. The level of intracellular triacylglycerol in two other I-FABP-transfected clones resembled that of control cells. However, secretion of triacylglycerol was markedly reduced in all the I-FABP-expressing cell lines. Our data suggest that increased expression of I-FABP leads to reduced triacylglycerol secretion in intestinal cells.

• Aas, Vigdis; Torblå, Siri; Andersen, Merethe H; Jensen, J. & Rustan, Arild (2002). Electrical stimulation improve insulin responses in a human skeletal muscle cell model of insulin resistance. Annals of the New York Academy of Sciences. ISSN 0077-8923. 967, s. 506–515. Vis sammendrag

  Myoblasts from human skeletal muscle were isolated from needle biopsy samples of the vastus lateralis of young and healthy volunteers. Contaminating fibroblasts were removed, and myoblasts were fused into differentiated multinucleated myotubes. These myotubes manifested both basal and insulin-stimulated (1-100 nM) glucose transport and glycogen synthesis. Insulin increased 2-deoxyglucose uptake 1.4-fold and glycogen synthesis 2.1-fold. Measurements of impedance of cell-covered gold electrodes (ECIS system) showed increased micromotion of caffeine-stimulated cells, showing their ability to contract. Acute electrical stimulation of the myotubes increased 2-deoxyglucose uptake by about 30 %. Treatment with high glucose concentrations (10-20 mM) for 2-8 days reduced both basal and insulin-stimulated glucose uptake. Maximal effect was seen already after 2 days treatment with 20 mM glucose. The baseline glucose uptake and glycogen synthesis were reduced by 35 %, insulin-stimulated glucose uptake by 25 % and glycogen synthesis by 39 %, respectively. Total cell content of glycogen was not changed by hyperglycemia. The insulin-stimulated glucose uptake in hyperglycemia treated cells was improved by electrical stimulation of the cells. In conclusion, a model of hyperglycemia has been established, and electrical stimulation improved insulin responses.

• Madsen, Lars; Guerre-Millo, Michele; Flindt, Esben N.; Berge, K.; Tronstad, Karl Johan & Bergene, Elin [Vis alle 14 forfattere av denne artikkelen] (2002). Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance. Journal of Lipid Research. ISSN 0022-2275. 43(5), s. 742–750. Vis sammendrag

  A high fat diet is associated with a wide range of metabolic abnormalities, including adiposity, dyslipidemia, hyperglycemia and insulin resistance. This study aimed to investigate whether the hypolipidemic, non-b-oxidizable fatty acid analogue, tetradecylthioacetic acid (TTA) could prevent high fat diet induced adiposity and insulin resistance. In Wistar rats fed a high fat diet, simultaneous feeding with TTA completely prevented the increase in epididymal- and retroperitoneal adipose tissue mass. Furthermore, TTA prevented the diet-induced development of insulin resistance as evidenced by a fully normal glucose tolerance test. Moreover, TTA prevented high fat diet induced elevated levels of fasting free fatty acids and postprandial triacylglycerols. In obese Zucker (fa/fa) rats, TTA treatment decreased the adipose tissue mass, lowered hyperglycemia and markedly improved insulin action on glucose utilization as determined by the intravenous glucose tolerance test. Additionally, TTA increased the mRNA levels of fatty acid transport protein, fatty acid binding protein and carnitine palmitoyltransferase I- and II. TTA was found to activate rodent peroxisome proliferator-activated receptor PPARa, PPARg and PPARd, but efficient activation of PPARg and PPARd required higher concentrations than those required for PPARa activation. In keeping with the ability of TTA to activate PPARa, TTA treatment increased hepatic mRNA levels of fatty acid metabolizing enzymes regulated by PPARa accompanied by increased hepatic mitochondrial b-oxidation and by a decreased fatty acid/ketone body ratio in plasma. In contrast to the effect on PPARa target genes, the expression of PPARg target genes in adipose tissue was not affected by TTA. Our results suggest that TTA-induced increase in hepatic fatty acid oxidation plays a major role in decreasing hepatic triacylglycerol synthesis and output resulting in a lowering of plasma triacylglycerol levels. This may underlay the ability of TTA to reduce the rate of accretion of fat stores and prevent the development of insulin resistance in peripheral tissues.

• Madsen, Lise; Guerre-Millo, Michele; Nørgaard Flint, Esben; Berge, Kjetil; Tronstad, Karl Johan & Bergene, Elin [Vis alle 14 forfattere av denne artikkelen] (2002). Tetradecylthioacetic acid prevents high fat diet induced adiposity and insulin resistance. Journal of Lipid Research. ISSN 0022-2275. 43(5), s. 742–750. Vis sammendrag

  Tetradecylthioacetic acid (TTA) is a non-beta-oxidizable fatty acid analog, which potently regulates lipid homeostasis. Here we evaluate the ability of TTA to prevent diet-induced and genetically determined adiposity and insulin resistance. In Wistar rats fed a high fat diet, TTA administration completely prevented diet-induced insulin resistance and adiposity. In genetically obese Zucker (fa/fa) rats TTA treatment reduced the epididymal adipose tissue mass and improved insulin sensitivity. All three rodent peroxisome proliferator-activated receptor (PPAR) subtypes were activated by TTA in the ranking order PPARalpha > PPARdelta > PPARgamma. Expression of PPARgamma target genes in adipose tissue was unaffected by TTA treatment, whereas the hepatic expression of PPARalpha-responsive genes encoding enzymes involved in fatty acid uptake, transport, and oxidation was induced. This was accompanied by increased hepatic mitochondrial beta-oxidation and a decreased fatty acid/ketone body ratio in plasma. These findings indicate that PPARalpha-dependent mechanisms play a pivotal role, but additionally, the involvement of PPARalpha-independent pathways is conceivable. Taken together, our results suggest that a TTA-induced increase in hepatic fatty acid oxidation and ketogenesis drains fatty acids from blood and extrahepatic tissues and that this contributes significantly to the beneficial effects of TTA on fat mass accumulation and peripheral insulin sensitivity.

• Rustan, Arild & Drevon, Christian A (2001). Fatty acids: structures and properties. Encyclopedia of Life Sciences. ISSN 1476-9506.
• Halvorsen, Bente; Rustan, Arild; Madsen, Lars; Reseland, Janne Elin; Berge, Rolf Kristian & Sletnes, P. [Vis alle 7 forfattere av denne artikkelen] (2001). Effect of long-chain n-3 and mono-unsaturated fatty acids on fatty acid oxidation and lipid composition in rats. Annals of Nutrition and Metabolism. ISSN 0250-6807. 45(1), s. 30–37. Vis sammendrag

  ammendrag Long-chain n-3 fatty acids and fat fish are reported, among multiple physiological properties, to enhance peroxisomal b-oxidation and affect triacylglycerol status. Long-chain n-3 and mono-unsaturated fatty acids are the main portion of fatty acids in fat fish. The individual effect of long-chain monounsaturated fatty acids on b-oxidation and fatty acid composition was tested and compared to the effect of n-3 polyunsaturated fatty acid and saturated fatty acids in a 3 weeks feeding experiment of rats. To explore the contribution from long-chain monounsaturated fatty acids in these aspects, the effect of long-chain n-3 and mono-unsaturated fatty acids on mitochondrial and peroxisomal b-oxidation was compared, as well as fatty acid composition of adipose tissue, liver and serum. Fatty acid oxidase, palmitoyltransferase I and II activities, the amount of serum lipids, and the fatty acid composition of lipid fractions from the organs were analysed. The peroxisomal b-oxidation was enhanced by the n-3 fatty acids, whereas a small, significant increase with the monounsaturated fatty acids was observed. There was a stimulation of the mitochondrial oxidation with the n-3 fatty acids, but monounsaturated fatty acids gave a small, non-significant decrease. With n-3 fatty acids there was a considerable decrease in the levels of serum triacylglycerol, phospholipids, free fatty acids and total cholesterol, while there was only minor effects of mono-unsaturated fatty acids. As judged from the fatty acid composition data, there was a mobilisation of n-3 fatty acids from the adipose tissue to liver and plasma with the n-3 diet. This observation was also seen with the n-3 fatty acid-free, monounsaturated fatty acid-enriched diet. In conclusion, mono-unsaturated fatty acids seemed to stimulate peroxisomal b-oxidation and triacylglycerol synthesis, whereas the mitochondrial oxidation was unaltered.

• Rustan, Arild (1999). Interaksjoner mellom legemidler, næringsstoffer og ernæringsstatus. I Bjørneboe, Gunn Elin; Drevon, Christian A & Norum, Kaare Reidar (Red.), Mat og medisin. Nordisk lærebok i generell og klinisk ernæring. Cappelen Damm Høyskoleforlaget. ISSN 82-7634-241-8. s. xx–xx.
• Gedde-Dahl, Ane; Bakillah, A.; Hussain, M.M. & Rustan, Arild (1999). Tetradecylthioacetic acid (a 3-thia fatty acid) impairs secretion of oleic acid-induced triacylglycerol-rich lipoproteins in CaCo-2 cells. Biochimica et Biophysica Acta. ISSN 0006-3002. 1438(1), s. 73–84.
• Berge, Rolf Kristian; Madsen, Lars; Vaagenes, H.; Tronstad, Karl Johan; Gottlicher, M. & Rustan, Arild (1999). In contrast with docosahexaenoic acid, eicosapentaenoic acid and hypolipidaemic derivatives decrease hepatic synthesis and secretion of triacylglycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation. Biochemical Journal. ISSN 0264-6021. 343(1), s. 191–197.
• Madsen, Lars; Rustan, Arild; Vaagenes, H.; Berge, K.; Dyrøy, E & Berge, Rolf Kristian (1999). Eicosapentaenoic acid and docosahexaenoic acid affect mitochondrial and peroxisomal fatty acid oxidation in relation to substrate preference. Lipids. ISSN 0024-4201. 34(9), s. 951–963.
• Fraser, D. A.; Thoen, J. E.; Rustan, Arild; Forre, O. & Kjeldsen-Kragh, Jens (1999). Changes in plasma free fatty acid concentrations in rheumatoid arthritis patients during fasting and their effect upon T-lymphocyte proliferation. Rheumatology (Sveits). ISSN 0080-2727. 38(10), s. 948–952.
• Madsen, Lise; Rustan, Arild C.; Wergedahl, Hege; Berge, Kjetil; Dyrøy, Endre & Berge, Rolf Kristian (1999). Eicosapentaenoic and docosahexaenoic acid affect mitochondrial and peroxisomal fatty acid oxidation in relation to substrate preference. Lipids. ISSN 0024-4201. 34(9), s. 951–963.
• Madsen, Lise; Rustan, Arild C.; Vaagenes, Hege; Berge, Kjetil; Dyrøy, Endre & Berge, Rolf Kristian (1999). Eicosapentaenoic and docosahexaenoic Acid Affect Mitochondrial and Peroxisomal Fatty Acid Oxidation in Relation to Substrate Preference. Lipids. ISSN 0024-4201. 34(9), s. 951–963.
• Berge, Rolf Kristian; Madsen, Lise; Vaagenes, Hege; Tronstad, Karl Johan; Göttlicher, Martin & Rustan, Arild C. (1999). In contrast with docosahexaenoic acid, eicosapentaenoic acid and hypolipidaemic derivatives decrease hepatic synthesis and secretion of triacyllycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation. Biochemical Journal. ISSN 0264-6021. 343, s. 191–197.
• Rustan, Arild; Hustvedt, Bo Egil & Drevon, Christian A (1998). Postprandial decrease in plasma unesterified fatty acids during n-3 fatty acid feeding is not caused by accumulation of fatty acids in adipose tissue. Biochimica et Biophysica Acta. ISSN 0006-3002. 1390(3), s. 245–257.

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• Thoresen, G. Hege; Simonsen, terje; Christensen, Hege; Johansen, Harald Thidemann; Kase, Eili Tranheim & Robertsen, Ida [Vis alle 9 forfattere av denne artikkelen] (2021). Basal farmakologi. Fagbokforlaget. ISBN 9788245033557. 405 s.
• Thoresen, G. Hege; Solberg, Rigmor; Johansen, Harald Thidemann; Kase, Eili Tranheim; Rustan, Arild Christian & Christensen, Hege [Vis alle 7 forfattere av denne artikkelen] (2020). Illustrert farmakologi. Fagbokforlaget. ISBN 9788245033564. 392 s.

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• Pirkmajer, Sergej; Garcia-Roves, Pablo M.; Rustan, Arild Christian & Chibalin, Alexander V. (2022). Editorial: Untangling energy metabolism in skeletal muscle: From physiology to pharmacology. Frontiers in Physiology. ISSN 1664-042X. 13. doi: 10.3389/fphys.2022.1113860.
• Viktorsson, Elvar Örn; Åstrand, Ove Alexander Høgmoen; Rustan, Arild; Thoresen, G. Hege; Kase, Eili Tranheim & Rongved, Pål (2015). Analogs of 22-S-hydroxycholesterol as potential Liver X Receptor-modulators: Synthesis and biological evaluation.
• Feng, Yuan Zeng; knabenes, Irlin Knivsland; Bakke, Siril S.; Lund, Jenny; Lee, Y.K. & kimmel, Alan [Vis alle 9 forfattere av denne artikkelen] (2015). Increased lipid oxidation and decreased lipid storage in myotubes lacking the lipid droplet binding protein perilipin2.
• Kong, Xiang Yi; Nesset, Cecilie Kåsi; Schjalm, Camilla; Løberg, Else Marit; Rustan, Arild & Thoresen, G. Hege [Vis alle 8 forfattere av denne artikkelen] (2014). NCU-G1GT/GT MICE: A LONG-LIVED MODEL FOR LIVER FIBROSIS.
• Feng, Yuan Zeng; knabenes, Irlin Knivsland; Lund, Jenny; Lee, Y.K.; kimmel, Alan & Thoresen, G. Hege [Vis alle 8 forfattere av denne artikkelen] (2014). Increased lipid oxidation and decreased lipid storage in myotubes lacking perilipin2.
• Kase, Eili Tranheim; Lund, Jenny; Feng, Yuan Zeng; Langleite, Torgrim Mikal; Aas, Vigdis & Jensen, Jan S. [Vis alle 11 forfattere av denne artikkelen] (2013). Effect of exercise on fatty acid and glucose metabolism in cultured human myotubes. Diabetologia. ISSN 0012-186X. 56, s. S250–S250.
• Smith, Robert; Johansen, Harald Thidemann; Jacobsen, Linn Løkken; Voreland, Anette Larsen; Rustan, Arild & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2013). Simvastatin inhibits legumain activity and processing in human myotubes.
• Covington, Jeffrey D.; Galgani, Jose E.; Rustan, Arild; Zhang, Zhengyu; Moro, Cedric & Smith, Steven R. [Vis alle 8 forfattere av denne artikkelen] (2013). Muscle perilipin 3 is reduced using in vitro and in vivo exercise models and negatively associated with exercise lipid oxidation. The FASEB Journal. ISSN 0892-6638. 27.
• Bakke, Siril Skaret; Feng, Yuan Zeng; Rustan, Arild; Hjelmesæth, Jøran; Thoresen, G. Hege & Aas, Vigdis (2012). Lower lipolysis to counteract the development of type 2 diabetes mellitus - evidence from myotubes established from extremely obese subjects.
• Aas, Vigdis; Bakke, Siril Skaret; Nikolic, Natasa; Hjelmesæth, Jøran; Thoresen, G. Hege & Rustan, Arild (2012). Altered energy metabolism in skeletal muscle cells derived from morbidly obese subjects.
• Bakke, Siril Skaret; Nikolic, Natasa; Rustan, Arild; Hjelmesæth, Jøran; Thoresen, G. Hege & Aas, Vigdis (2012). ALTERED ENERGY METABOLISM IN SKELETAL MUSCLE CELLS DERIVED FROM MORBIDLY OBESE INDIVIDUALS. Vis sammendrag

  Introduction: Obesity is strongly associated with insulin resistance and type 2 diabetes (T2D). It has been revealed that less than 1 out of 3 morbidly obese subjects have T2D (Obes Surg 2010; 20:302-7), indicating that many morbidly obese subjects possess certain characteristics that protect them against developing T2D. Skeletal muscle is an important organ involved in fatty acid and glucose metabolism and therefore one of the organs where insulin resistance is most prominent. Metabolic flexibility is defined as the muscle’s ability to change energy metabolism between fed and fasted conditions, and this ability is reduced in insulin resistance and T2D. Methods: We examined fatty acid and glucose metabolism as well as metabolic flexibility in human skeletal muscle cells using radiolabeled precursors. The cells were derived from lean healthy subjects (BMI 23±0.9 kg/m2), morbidly obese with normal glucose tolerance (BMI 44±2.0 kg/m2) and morbidly obese subjects with T2D (BMI 43±1.5 kg/m2). Results: A 2-fold increase in fatty acid metabolism was observed in cells established from morbidly obese subjects (measured as accumulation and oxidation of oleic acid) and a approximately 40% lower metabolic flexibility (measured as the ability to switch from fatty acid to glucose oxidation) compared to cells from lean subjects. Triacylglycerol lipolysis was 30% higher for obese T2D subjects compared to the other groups. Conclusion: Muscle cells derived from morbidly obese showed increased lipid metabolism, but had a lower metabolic flexibility than cells from lean. Obese subjects with T2D had increased lipolysis, which may be important for development of T2D. Conflict of Interest None disclosed Funding Norwegian Research Council, Norwegian Diabetes Foundation, Freia Chocolade Fabriks Medical Foundation and Anders Jahre’s Foundation.

• Bakke, Siril Skaret; Nikolic, Natasa; Rustan, Arild; Hjelmesæth, Jøran; Thoresen, G. Hege & Aas, Vigdis (2012). Altered energy metabolism in skeletal muscle cells derived from morbidly obese donors.
• Bakke, Siril Skaret; Nikolic, Natasa; Moro, Cedric; Lauvhaug, Line; Hessvik, Nina Pettersen & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2011). DIFFERENT HANDLING OF PALMITIC ACID AND OLEIC ACID IN HUMAN SKELETAL MUSCLE CELLS.
• Bakke, Siril Skaret; Nikolic, Natasa; Moro, Cedric; Lauvhaug, Line; Hessvik, Nina Pettersen & Thoresen, G. Hege [Vis alle 7 forfattere av denne artikkelen] (2011). Different handling of palmitic acid and oleic acid in human skeletal muscle cells.
• Lauvhaug, Line; Bakke, Siril Skaret; Thoresen, G. Hege & Rustan, Arild (2011). Different handling of oleic, palmitic, linoleic and eicosapentaenoic acids in cultured human skeletal muscle cells.
• Halle, Ingeborg F.; Nikolic, Natasa; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Aas, Vigdis (2011). Electrical pulse stimulation of cultured human skeletal muscle cells as a model of exercise in vitro.
• Dembinska-Kiec, A.; Knapp, A.; Kiec-Wilk, B.; Sliwa, A.; Czech, U. & Korczynska, M. [Vis alle 7 forfattere av denne artikkelen] (2010). Metabolism of endothelial and adipose stromal vascular (SVF) fraction in the presence of fatty acids. European Journal of Clinical Investigation. ISSN 0014-2972. 40, s. 78–79.
• Nikolic, Natasa; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Aas, Vigdis (2010). Chronic electrical pulse stimulation of cultured human skeletal muscle cells as an in vitro model of exercise.
• Nikolic, Natasa; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Aas, Vigdis (2010). Energimetabolismen i humane skjelettmuskelceller - Utvikling av in vitro treningsmodell.
• Nikolic, Natasa; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Aas, Vigdis (2010). Chronic electrical pulse stimulation of cultured human skeletal muscle cells as an in vitro model of exercise.
• Hessvik, Nina Pettersen; Bakke, Siril Skaret; Thoresen, G. Hege; Rustan, Arild & Kase, Eili Tranheim (2010). Effects of 22-S-hydroxycholesterol (a liver X receptor modulator) on Lipid Metabolism. Vis sammendrag

  Liver X receptors (LXRs) play a crucial role in regulation of cholesterol, lipid and carbohydrate metabolism. 22-S-hydroxycholesterol (22-S-HC) has been shown to act as an LXR antagonist and to reduce de novo lipogenesis and lipid accumulation, as well as to increase glucose uptake in human skeletal muscle cells (myotubes). The aim of the present study was to further investigate the effects of 22-S-HC on lipid and glucose metabolism in human-derived cell lines from metabolic active tissues important for development of obesity and type 2 diabetes. We also wanted to explore the effects of 22-S-HC on plasma lipids in vivo in rats. The results show that de novo lipogenesis from [14C]acetate was decreased by 22-S-HC in myotubes and HepG2 (liver) cells, whereas increased in SGBS cells (adipocytes) and unaffected in CaCo-2 cells (intestinal cells). This was partly reflected by regulation of the lipogenic genes, sterol regulatory element binding transcription factor 1 (SREBF1) and fatty acid synthase (FASN), as measured by RT qPCR. Live imaging showed that the number of lipid droplets (LDs) was increased in SGBS cells, decreased in HepG2 cells and unaffected in myotubes by 22-S-HC treatment. Furthermore, exposure to 22-S-HC increased and tended to increase glucose uptake in myotubes and SGBS cells, respectively. However, apoA1-dependent cholesterol efflux was unaffected by 22-S-HC. These observations show that 22-S-HC differently affect distinct LXR-regulated processes, and that 22-S-HC not solely acts as an antagonist to LXR, but also stimulate some LXR-regulated processes. Furthermore, the results suggest that 22-S-HC might reduce ectopic fat accumulation and result in a more favorable lipid distribution. To investigate the effects of 22-S-HC in vivo, high-fat fed Wistar rats were given 30 mg/kg/day of 22-S-HC for 3 weeks. The 22-S-HC treated rats showed significantly reduced body weight gain compared to the control animals and reduced plasma levels of free fatty acids and triacylglycerol. Therefore, compounds with properties similar to 22-S-HC may be of importance in search towards better treatments for obesity and type 2 diabetes.

• Bakke, Siril Skaret; Hessvik, Nina Pettersen; Thoresen, G. Hege & Rustan, Arild (2010). The impact of the n-3 fatty acid eicosapentaenoic acid (EPA) on metabolic switching in human skeletal muscle cells. Vis sammendrag

  Our recent studies with differentiated human skeletal muscle cells (myotubes) suggests a positive role for the n-3 fatty acid eicosapentaenoic acid (EPA) compared to the other monounsaturated and saturated fatty acids (FAs) in improving overall metabolic switching in skeletal muscle in vitro. This might contribute to the beneficial health effects of dietary intake of very long-chain n-3 fatty acids. In a study using myotubes established from lean healthy donors we showed that incubation of EPA for one day increased suppressibility, the ability of acute glucose to suppress FA oxidation. Substrate-regulated flexibility, the ability to increase FA oxidation when changing from a high glucose, low fatty acid condition (“fed”) to a high fatty acid, low glucose (“fasted”) condition, was also increased by EPA. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was enhanced after pretreatment with several FAs (EPA, linoleic acid (LA) and palmitic acid (PA)). EPA present in the cell after one day was significantly less than the other FAs, probably due to a higher oxidation rate. Yet, EPA, LA and oleic acid (OA) treatment increased the number of lipid droplets (LDs) in myotubes. LD volume and intensity, as well as mitochondrial mass were independent of FA pretreatment. Microarray and PCR analysis showed that EPA regulated more genes than the other FAs, and that specific pathways involved in carbohydrate metabolism were induced only by EPA. The present study suggests a favorable effect of EPA on skeletal muscle metabolic switching. Additional experiments with ALA (α-linolenic acid) and DHA (docosahexaenoic acid) indicated that the metabolic effects could be due to a general quality of n-3 FAs. Based on findings from this study we also suggest the use of three parameters called suppressibility, adaptability and substrate-regulated flexibility in functional studies of fuel selection and energy metabolism in cell cultures. References: Hessvik NP, Bakke SS et al, “Metabolic switching of human myotubes is improved by n-3 fatty acids.”, J Lipid Res. 2010 Aug;51(8):2090-104.

• Bakke, Siril Skaret; Hessvik, Nina Pettersen; Thoresen, G. Hege & Rustan, Arild (2010). HANDLING OF PALMITIC ACID AND OLEIC ACID IN HUMAN SKELETAL MUSCLE CELLS. Vis sammendrag

  Obesity seems to be associated with type of dietary fat, and a positive association with saturated fatty acids (SFA) and a negative association with monounsaturated fatty acids (MUFA) have been found. In human skeletal muscle cells, SFA is reported to preferentially accumulate as diacylglycerol (DAG) and ceramides, while MUFA is reported to preferentially accumulate as triacylglyserol (TAG). In accordance to this, we have previously shown that the number of lipid droplets (LDs) is two-fold higher after pretreatment with oleic acid (OA) than palmitic acid (PA). PA has also been found to be more oxidized than OA. We wanted to study the handling of OA and PA in human myotubes, regarding uptake, oxidation and storage. Satellite cells were isolated from biopsy samples from M. obliquus internus abdominis and differentiated into multinucleated myotubes. Myotubes were pretreated for 24 h with 100 μM OA/PA, and the metabolism of [14C] OA/PA was studied. For imaging with fluorescence microscope, myotubes were stained with Bodipy and Hoescht, and LDs and nuclei were counted. Our results show that in human myotubes more OA than PA was stored, while PA was oxidized to a higher degree than OA. OA was stored mostly as TAG, while more PA than OA was stored in phospholipids. When long fatty acyl CoA synthetase was inhibited by Triacsin C, the storage of OA in TAG and DAG was reduced, but storage of PA remained unchanged. More OA than PA was subject to lipolysis; however the lipolysis seemed to parallel the storage in LDs. Thus, lipolysis might not be dependent on saturation of fatty acids stored but on the amount of lipids stored. In conclusion, our results indicate that PA has a higher turnover and is more available for oxidation than OA. This might be of importance in further studies of the link between intracellular lipids and the development of insulin resistance.

• Aas, Vigdis; Hessvik, Nina Pettersen; Thoresen, G. Hege & Rustan, Arild (2010). Chronic hyperglycemia impairs mitochondrial function in human myotubes.
• Rustan, Arild (2010). The impact of eicosapentaenoic acid (EPA) on regulation of fatty acid metabolism, metabolic flexibility and gene expression in human skeletal muscle cells. Vis sammendrag

  Our recent studies with differentiated human skeletal muscle cells (myotubes) suggests a positive role for eicosapentaenoic acid (EPA) compared to the other fatty acids (FAs) in improving overall energy metabolism and metabolic switching in skeletal muscle, which may contribute to the beneficial effects of dietary intake of very long-chain n-3 fatty acids. In a study using myotubes established from lean donors we showed that EPA increased suppressibility, the ability of acute glucose to suppress FA oxidation. Substrate-regulated flexibility, the ability to increase FA oxidation when changing from a high glucose, low fatty acid condition (“fed”) to a high fatty acid, low glucose (“fasted”) condition, was increased by EPA. Adaptability, the capacity to increase FA oxidation with increasing FA availability, was enhanced after pretreatment with EPA, linoleic acid (LA) and palmitic acid (PA). EPA per se accumulated less in the cells, however, EPA, LA and oleic acid (OA) treatment increased the number of lipid droplets (LDs) in myotubes. LD volume and intensity, as well as mitochondrial mass were independent of FA pretreatment. Microarray and PCR analysis showed that EPA regulated more genes than the other FAs and specific pathways involved in carbohydrate metabolism were induced only by EPA. The present study suggest a favorable effect of EPA on skeletal muscle metabolic switching and glucose utilization. Additional experiments with ALA and DHA indicated that the metabolic effects could be due to a general quality of n-3 FAs. Based on finding from this study we also suggest the use of three parameters called suppressibility, adaptability and substrate-regulated flexibility in functional studies of fuel selection and energy metabolism in cell cultures. In another study we wanted to identify the potential effects of EPA and a synthetic fatty acid derivative (TTA) on energy metabolism, insulin resistance and gene expression (PCR). Here we compared the effects of EPA, TTA, and OA in myotubes established from obese individuals with type 2 diabetes and obese healthy control subjects. Our results suggest that 1) mitochondrial dysfunction in diabetic myotubes was caused by disturbances downstream of fatty acid β-oxidation; 2) EPA promoted accumulation of triacylglycerol (TAG), enhanced β-oxidation, and increased glucose oxidation; and 3) TTA improved complete palmitic acid oxidation in diabetic myotubes, opposed increased lipid accumulation, and increased glucose oxidation.

• Rustan, Arild Chr.; Wettergreen, Marianne; Hessvik, Nina; Thoresen, G. Hege & Aas, Vigdis (2010). Chronic hyperglycaemia impairs metabolic switching of human myotubes.
• Aas, Vigdis; Hessvik, Nina; Thoresen, Hege & Rustan, Arild Chr. (2010). Chronic hyperglycaemia impairs mitochondrial function in human myotubes.
• Bakke, Siril Skaret; Hessvik, Nina Pettersen; Fjørkenstad, Anne; Koster, Gerbrand; Rustan, Arild & Thoresen, G. Hege (2009). Eicosapentaenoic acid improves metabolic switching of human myotubes. Vis sammendrag

  In skeletal muscle, glucose oxidation dominates in the fed state, while fat oxidation increases both during fasting and during sustained exercise. Metabolic flexibility is the ability to switch from predominantly lipid oxidation during fasting conditions to suppression of lipid oxidation and increased glucose oxidation during feeding conditions. Loss of metabolic flexibillity is related to insulin resistance in skeletal muscle. Skeletal muscle (myotubes) store fat in lipid droplets and is the major tissue for lipid and glucose oxidation in the body. We have tested whether treatment with different fatty acids including eicosapentaenoic acid (EPA), linoleic acid (LA), palmitic acid (PA) and oleic acid (OA), as well as activation of the nuclear receptor liver X receptor, could modify metabolic switching of myotubes and whether these changes is correlated to changes in mitochondria or lipid droplets in the cells. Methods used are radiolabeled substrate oxidation assays and live imaging of lipid droplets and mitochondria. Myotubes were stained with Hoescht, Bodipy 493/503 (lipid droplets) and Mitotracker®Red FM and live imaging was performed using the Scan^R high throughput microscope (Olympus) at the Department of Molecular Biosciences, UiO, NorMIC imaging node. Number, size and size distribution of lipid droplets and mitochondrial content in myotubes dependent on pretreatment was quantified. Results showed that EPA pretreatment of myotubes increased metabolic switching. Furthermore, preatreatment with EPA, as well as with OA and LA and activation of the nuclear receptor liver X receptor increased the number of lipid droplets per nucleus. Lipid droplet size, size distribution and mitochondrial content were independent of pretreatment conditions. This study suggests a possible favorable effect of EPA on skeletal muscle metabolic switching and glucose utilization.

• Aas, Vigdis; Wettergreen, Marianne; Hessvik, Nina P.; Thoresen, G. Hege & Rustan, Arild Chr. (2009). Chronic hyperglycemia reduces myotube mitochondrial function without changing mitochondrial gene expression or mitochondrial content.
• Corpeleijn, E; Hessvik, Nina Pettersen; Blaak, EE; Thoresen, G. Hege; Gaster, M & Rustan, Arild (2008). Utilization of intramyocellular lipids for oxidation in human skeletal muscle cells from lean and type 2 diabetic subjects. Diabetologia. ISSN 0012-186X. 51, s. S303–S303.
• Rustan, Arild (2007). Legemidler ved behandling av fedme.
• Aas, Vigdis; Wensaas, Andreas J.; Thoresen, G. Hege; Hallèn, Stefan & Rustan, Arild Chr. (2007). Chronic hyperglycemia impairs flexibility related to fatty acid metabolism in human myotubes.
• Rustan, Arild (2006). Insulinresistens i humane skje-lettmuskelceller i kultur: Gunstige metabolske effekter av omega-3 fettsyrer. Toksikologen. ISSN 1504-5773. 2.
• Rustan, Arild (2006). FATTY ACID-MEDIATED ACCUMULATION OF TRIACYLGLYCEROL IN MYOTUBES FROM TYPE 2 DIABETICS IS REDUCED BY A PAN-PPAR AGONIST TETRADECYL-THIOACETIC ACID (TTA).
• Rustan, Arild (2006). CELL BASED MULTI-WELL ASSAYS FOR DETECTION OF SUBSTRATE ACCUMULATION AND OXIDATION.
• Rustan, Arild (2006). Metabolism and biological effects of n-3 fatty acids.
• Aas, Vigdis; Wensaas, Andreas J.; Thoresen, G. Hege & Rustan, Arild Chr. (2006). Chronic hyperglycaemia impairs flexibility related to fatty acid metabolism in human myotubes.
• Florholmen, Geir; Thoresen, G. Hege; Rustan, Arild Chr.; Jensen, Jørgen; Christensen, Geir & Aas, Vigdis (2006). Leukaemia Inhibitory Factor Stimulates Glucose Transport in Isolated Cardiomyocytes and Induces Insulin Resistance after Chronic Exposure.
• Kase, Eili Tranheim; Wensaas, Andreas J.; Aas, Vigdis; Andersen, B; Højlund, Kurt & Levin, K [Vis alle 11 forfattere av denne artikkelen] (2006). A role for LXR in lipid and glucose metabolism in human skeletal muscle.
• Florholmen, Geir; Thoresen, G. Hege; Rustan, Arild; Jensen, Jørgen; Christensen, Geir Arve & Aas, Vigdis (2006). Leukaemia inhibitory factor stimulates glucose transport in isolated cardiomyocytes and induces insulin resistance after chronic exposure.
• Iversen, PO; Sorensen, DR; Berge, Rolf Kristian; Rustan, AC & Drevon, CA (2005). A sulfur-substituted fatty acid analog improves survival and impairs metastasis in rat models of acute leukemia. Experimental Hematology. ISSN 0301-472X. 33.
• Rustan, Arild & Drevon, Christian A (2005). Fatty acids: structures and properties. Encyclopedia of Life Sciences. ISSN 1476-9506. Vis sammendrag

  Fatty acids, both free and as part of complex lipids, play a number of key roles in metabolism – as a major metabolic fuel (storage and transport of energy), as essential components of all membranes and as gene regulators. In addition, dietary lipids provide polyunsaturated fatty acids (PUFAs) that are precursors of powerful locally acting metabolites, i.e. the eicosanoids. As part of complex lipids, fatty acids are also important for thermal and electrical insulation, and for mechanical protection. Moreover, free fatty acids and their salts may function as detergents and soaps owing to their amphiphatic properties and formation of micelles.

• Rustan, Arild (2005). A role for LXR in lipid and glucose metabolism in human skeletal muscle.
• Rustan, Arild (2005). A role for LXR in lipid and glucose metabolism in human skeletal muscle. Vis sammendrag

  Liver X receptors (LXRs) are well known as important actors in cholesterol and lipid metabolism, and have also recently been connected to glucose metabolism. The functional role of LXRs in human skeletal muscle is at present mostly unknown. We have studied the effect of chronic ligand activation by a synthetic LXR agonist (T0901317) on lipid and glucose metabolism in human myotubes. Our results demonstrate that activation of LXRs increased uptake, distribution into complex cellular lipids and oxidation of palmitate, and uptake and oxidation of glucose in myotubes. Consistently, activation of LXRs induced the expression of relevant genes; fatty acid translocase (CD36/FAT), glucose transporters (GLUT1/GLUT4), sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor (PPARgamma), carnitine palmitoyltransferase-1 (CPT-1) and uncoupling proteins (UCP2/UCP3). Interestingly, in response to activation of LXRs, myotubes from type 2 diabetic subjects showed an elevated uptake and incorporation of palmitate into complex lipids, but absence in palmitate oxidation to CO2. Moreover, results also showed that 22-hydroxycholesterols (22-R-HC and 22-S-HC) had effects on important LXR target genes both for glucose and lipid metabolism. 22-R-HC, which could be an endogenous LXR ligand in human muscle, also increased the mRNA expression of some LXR target genes, but regulated lipid and glucose metabolism differently than T0901317 with less formation of lipids (similar to untreated cells). 22-S-HC was not an inactive ligand in human myotubes, but repressed certain genes involved in lipogenesis and lipid handling, reduced accumulation of complex lipids and increased basal glucose uptake. Taken together, these results provide evidence for a functional role of LXRs in lipid and glucose metabolism and energy uncoupling in human myotubes. Furthermore, these data suggest that increased intramyocellular lipid content in type 2 diabetic subjects may involve an altered response to activation of components in the LXR pathway. Reference: Kase ET, Wensaas AJ, Aas V, Højlund K, Levin K, Thoresen GH, Beck-Nielsen H, Rustan AC, Gaster M. Diabetes, 2005, 54:1108-1115

• Florholmen, Geir; Aas, Vigdis; Rustan, Arild; Lunde, Per Kristian; Straumann, Nadine & Eid, Hilde [Vis alle 10 forfattere av denne artikkelen] (2005). Leukemia inhibitory factor reduces contractile function and induces alterations in energy metabolism in isolated cardiomyoctyes.
• Florholmen, Geir; Thoresen, G. Hege; Rustan, Arild Chr.; Jensen, Jørgen; Christensen, Geir & Aas, Vigdis (2005). Leukaemia inhibitory factor stimulates glucose transport in isolated cardiomyocytes and induces insulin resistance after chronic exposure.
• Thoresen, G. Hege; Kase, Eili Tranheim; Wensaas, Andreas J.; Aas, Vigdis; Andersen, B & Højlund, Kurt [Vis alle 11 forfattere av denne artikkelen] (2005). A role for LXR in lipid metabolism in human skeletal muscle.
• Rustan, Arild (2004). Increased fatty acid and glucose metabolism in cultured human myotubes after treatment with the Liver X Receptor (LXR) agonist T0901317.
• Rudberg, Ida; Florholmen, Geir; Jensen, Jørgen; Rustan, Arild Chr. & Aas, Vigdis (2004). Electrical stimulation of human skeletal muscle cells as a model of exercise; effects on insulin signalling and glucose metabolism.
• Aas, Vigdis; Kase, Eili Tranheim; Wensaas, Andreas J.; Gaster, Michael & Rustan, Arild Chr. (2004). Lipid metabolism in human skeletal muscle cells.
• Aas, Vigdis; Kase, Eili Tranheim; Wensaas, Andreas J.; Thoresen, G. Hege & Rustan, Arild Chr. (2004). Lipid metabolism in human skeletal muscle cells.
• Wensaas, Andreas & Rustan, Arild (2003). Tetradecylthioacetic acid (TTA) increases fatty acid oxidation without impairment of glucose utilization in cultured human myotubes. Vis sammendrag

  The hypolipidemic action of the sulfur substituted fatty acid analogue tetradecylthioacetic acid (TTA) is well documented. TTA also decreases hyperglycemia and markedly improves insulin action in animal models of insulin resistance. Moreover, TTA treatment of rats increases insulin-stimulated glucose uptake in skeletal muscle, suggesting that it also influences glucose homeostasis in a favourable way. Based on these observations we studied the effect of TTA on lipid and glucose metabolism in cultured human skeletal muscle cells from healthy young as well as from obese type 2 diabetic subjects (T2D). Satelitte cells (myoblasts) were isolated from the M. vastus lateralis, and fused to differentiated multinucleated myotubes for 6 days. Fatty acid metabolism was studied using 14C-palmitic acid (PA), glucose transport determined using 3H-2-deoxyglucose and glucose oxidation with 1-14C-glucose. Preincubation of control and T2D myotubes with TTA (50�100 µM) for 4 days during differentiation resulted in a 20-30 % increase in fatty acid beta-oxidation both under basal conditions and with acute insulin (100 nM) stimulation. At the same time PA esterification into triacylglycerol (TAG) was reduced by approximately 30 %. The effect of TTA on PA oxidation and TAG formation completely disappeared by addition of etomoxir (4 µM) which is an inhibitor of mitochondrial fatty acid oxidation. On the other hand, basal as well as insulin-stimulated glucose uptake was 1.4-fold increased after pretreatment with TTA both in control and T2D myotubes. Moreover, oxidation of glucose to carbondioxide was also slightly increased after exposure to TTA. Taken together our data suggest that TTA have distinct effects on skeletal muscle causing increased total oxidative capacity in control as well as T2D myotubes. At the same time, TTA prevents TAG accumulation in the cells and increases glucose uptake. These effects may be important for the lipid-lowering and antidiabetic action of TTA.

• Florholmen, G.; Aas, Vigdis; Rustan, Arild; Ødegaard, Annlaug; Andersson, Kristin Brevik & Christensen, Geir Arve (2003). The cytokine leukemia inhibitory factor is an inducer of contractile dysfunction.
• Rustan, Arild & Aas, Vigdis (2003). Redistribution of lipids in cultured myotubes established from T2D subjects - evidence for genetic defects in lipid oxidation in skeletal muscles. Vis sammendrag

  Insulin resistance in skeletal muscle in vivo is associated with impaired glucose transport and glycogen synthesis, which may be linked to lipid accumulation and reduced lipid oxidation. However, it is still uncertain whether observed changes in lipid metabolism represent an adaptive compensation at the cellular level or a direct expression of a primary i.e. genetic trait. Studies in cultured human myotubes may solve this problem since genetic defects will be preserved and expressed also during culture in vitro. In the present study we measured palmitate (PA, 0.6 mM) uptake, PA oxidation and the incorporation of PA into complex cellular lipids in myotubes established from 10 type 2 diabetic (T2D) subjects and 10 matched controls at basal physiological conditions (5.0 mM glucose, 25 pM insulin) and after an acute insulin stimulation (1 µM) to clarify wheather lipid metabolism express defects of genetic origin. Results: Total lipid uptake was similar in myotubes established from the two groups at basal conditions (117.7±16.3 vs 153.6±8.9 nmol/mg cell protein/4h, control vs T2D, p=0.08). However, complete palmitate oxidation was lower in myotubes established from diabetic subjects (5.9±0.6 vs 4.3±0.5 nmol/mg cell protein/4h, p<0.03). Furthermore, the palmitate incorporation into phospholipids was increased in myotubes established from type 2 diabetic subjects (50.0±5.6 vs 68.0±6.6 nmol/mg cell protein/4h, p=0.03). On the other hand, the incorporation of palmiate into diacylglycerol, triacylglyceroland sum of cellular lipid was significantly stimulated by insulin in both study groups (p<0.01), but there was no difference between groups (p>0.05). These findings are consistent with a primary determined redistibution of palmitate from oxidation to accumulation in myotubes established from type 2 diabetic subjects. Thus, our data may explain the reduced lipid oxidation and increased lipid content seen in vivo in skeletal muscles of type 2 diabetic subjects, which may be of genetic origin.

• Rustan, Arild; Solberg, Roger; Reseland, Janne Elin; Andersen, Merethe H; Drevon, Christian A & Aas, Vigdis (2002). Fatty Acids Modulate Leptin And Leptin Receptor (OB-Rb) Gene Expression And Leptin Secretion In Cultured Human Skeletal Muscle Cells. Vis sammendrag

  Background and Aims: Leptin is a hormone primarily secreted by adipocytes that plays a pivotal role in regulating food intake, energy expenditure and neuroendocrine function. Leptin stimulates oxidation of fatty acids and uptake of glucose, and prevents accumulation of lipids in nonadipose tissues. Inducible leptin expression in skeletal muscle cells (L6 rat cells) in response to insulin and glucosamine has been reported (Wang et al., Nature 1998, 393: 684-8). Based on this observation, we examined if leptin is present in skeletal muscle cells from human biopsies, and also if leptin and its receptor (OB-Rb) could be modulated by hormones, fatty acids and other energy substrates. Materials and Methods: Myoblasts were isolated from the vastus lateralis of young healthy volunteers and fused to differentiated multinucleated myotubes. MessengerRNA (mRNA) was isolated by magnetic beads (Dynal), and quantitative RT-PCR was performed using GeneAmp EZ rTth RNA PCR kit (Perkin Elmer) with 32P-dCTP. Relative abundance of phenotype marker mRNAs was calculated as a-tubulin cDNA ratio. Concentration of leptin in cell culture media was measured by a competitive radioimmunoassay (Linco Research). Glucose transport was measured after preincubation with fatty acids using 3H-2-deoxyglucose ± insulin (100 nM) and cytochalasin B. Results: Leptin was expressed in differentiated myotubes, and both expression (mRNA) and secretion were changed after incubation with 0.1-0.6 mM of fatty acids for 24 and 48 h. Oleic acid (OA) and eicosapentaenoic acid (EPA 20:5 n-3) increased leptin secretion to the culture medium, with the strongest effect of OA after 48 h incubation. We also observed that incubation with palmitic acid (PA), OA and EPA for 24 and 48 h increased leptin mRNA expression, whereas the leptin receptor (OB-Rb) mRNA expression was reduced 40-50 % by EPA. Moreover, the effect of these fatty acids on basal and insulin-stimulated glucose metabolism was also examined. Preincubation with PA and OA (0.6 mM for 24 h) induced insulin resistance assessed by decreased insulin-stimulated 2-deoxyglucose transport, when compared to fatty acid-free controls. EPA did not reduce insulin-stimulated glucose transport, and caused a 2-fold increase in basal as well as insulin-stimulated glucose transport. Conclusion: We have for the first time demonstrated leptin expression in human skeletal muscle cells. Furthermore, this is the first documentation of regulation of OB-Rb in any tissue examined. The physiological effect of fatty acids on the leptin axis in muscle cells needs further studies. We focus on how fatty acids affect leptin, OB-Rb and their signalling pathways in glucose and lipid metabolism.

• Rustan, Arild; Solberg, Rigmor; Reseland, Janne Elin; Andersen, Merethe H; Drevon, Christian A & Aas, Vigdis (2002). FATTY ACIDS MODULATE LEPTIN AND LEPTIN RECEPTOR (OB-RB) GENE EXPRESSION AND LEPTIN SECRETION IN CULTURED HUMAN SKELETAL MUSCLE CELLS. Vis sammendrag

  Leptin is a hormone primarily secreted by adipocytes that plays a pivotal role in regulating food intake, energy expenditure and neuroendocrine function. Leptin stimulates oxidation of fatty acids and uptake of glucose, and prevents accumulation of lipids in nonadipose tissues. Inducible leptin expression in skeletal muscle cells (L6 rat cells) in response to insulin and glucosamine has been reported (Wang et al., Nature 1998, 393: 684-8). Based on this observation, we examined if leptin is present in skeletal muscle cells from human biopsies, and also if leptin and its receptor (OB-RB) could be modulated by hormones, fatty acids and other energy substrates. Leptin was expressed in differentiated myotubes, and both expression (mRNA) and secretion were changed after incubation with 0.1-0.6 mM of fatty acids for 24 and 48 h. Oleate (OA) and eicosapentaenoic acid (EPA 20:5 n-3) increased leptin secretion to the culture medium, with the strongest effect of OA after 48 h incubation. We also observed that incubation with palmitate (PA), OA and EPA for 24 and 48 h increased leptin mRNA expression, whereas the leptin receptor (OB-RB) mRNA expression was reduced 40-50 % by EPA. Moreover, the effect of these fatty acids on basal and insulin-stimulated glucose metabolism was also examined. Preincubation with PA and OA (0.6 mM for 24 h) induced insulin resistance assessed by decreased insulin-stimulated 2-deoxy-glucose transport, when compared to fatty acid-free controls. EPA on the other hand, did not reduce insulin-stimulated glucose transport, and caused a 2-fold increase in basal as well as insulin-stimulated glucose transport. We have for the first time demonstrated leptin expression in human skeletal muscle cells. Furthermore, this is the first documentation of regulation of OB-RB in any tissue examined. The physiological effect of fatty acids on the leptin axis in muscle cells needs further studies. We focus on how fatty acids affect leptin, OB-RB and their signalling pathways in glucose and lipid metabolism.

• Howe, P.; Hammervold, T.; Meyer, B.; Rustan, Arild & Calvert, D. (2002). Omega-3 supplementation improves drug-treatment of hyperlipidaemia. Vis sammendrag

  Preliminary data indicated that combining fish oil supplementation with statin therapy may enhance the cholesterol-lowering effect of the drug as well as improving plasma triglycerides (Howe et al, Australian Atherosclerosis Society, 1998). We sought to confirm this effect in 45 statin-treated patients with persistent mild hypertriglyceridaemia (avg. 2.2 mmol/L) who were randomised to take 4 g/day or 8 g/day of either tuna oil (HiDHA, Clover Corporation) or olive oil (placebo) for 6 months. Plasma lipids were assessed initially and after 3 and 6 months in 40 subjects who completed the trial. Plasma triglycerides were reduced 13% by 4g and 27% by 8g of fish oil. Moreover, there was a marginally significant 8% decrease in plasma total cholesterol (TC) with 8g of fish oil, even though TC was already well controlled by the statin therapy (avg 4.5 mmol/L). There was no change in TC with the 4g dose. The extent of reduction correlated strongly (r = -0.84) with initial TC levels; the reduction was 13% (p = 0.02) in those subjects (10 per treatment group) with initial TC > 3.8 mmol/L. In this subset, plasma VLDL, IDL and LDL were isolated and assayed for cholesterol and apolipoprotein B. Fish oil tended to lower cholesterol and apoB in VLDL and raise both in LDL. There were no significant changes in IDL-cholesterol, IDL-apoB and HDL-cholesterol. In conclusion, a high intake of DHA-rich fish oil can further improve plasma lipids in patients taking statins and may be preferable to drug combinations for treatment of dyslipidaemia.

• Madsen, Lise; Berge, Rolf Kristian; Guerre-Millo, Michele; Berge, Kjetil; Bergene, Elin & Flindt, Esben N. [Vis alle 13 forfattere av denne artikkelen] (2001). Expression of PPARa target genes improve insulin action and reduce adiposity.
• Rustan, Arild & Storlien, Len H. (2001). Membrane lipids, storage lipids and insulin action. Vis sammendrag

  Skeletal muscle is the most important tissue for insulin-stimulated glucose metabolism and plays a major role, as well, in lipid metabolism. The liver is the primary organ of endogenous glucose production. Between them, these organs are predominant players in whole-body insulin action. While considerable advances have been made in eludicating the insulin-signalling cascade, the metabolic basis of insulin resistance is still incompletely understood. Two lipid-related variables, the fatty acid composition of phospholipid, the major membrane structural lipid, and the amount and location of accumulated storage lipid have both been closely linked to insulin action in both skeletal muscle and liver, and in both experimental animal and human studies. The general observation of impaired insulin action with increased saturation of membrane lipid has now been made under numerous conditions. Mechanisms are still not entirely clear, but may include both direct ones, eg, the protein kinase B (PKB) and/or protein kinase C (PKC) signalling systems, or indirect ones via changes in the physiochemical properties of membranes and hence either changes in membrane protein intrinsic activity or passive ion leakiness and thus cellular energy requirements. Similarly, the linkage of increased storage lipid with insulin resistance has been confirmed and shown, by both non-invasive imaging and direct measurement, to result from triacylglycerol actually within muscle myocytes in the case of skeletal muscle. Factors which control intramyocyte lipolysis and production, for example, of long-chain acyl CoA (LCACoA) and diacylglycerol (DAG) are likely to prove critical to modulation of insulin action. In summary, lipids play multiple roles in insulin action and the complete understanding of these processes will teach us much about how to ameliorate insulin resistance.

• Howe, P.R.C.; Hammervold, T.; Meyer, B.; Rustan, Arild & Calvert, G.D. (2001). EFFECTS OF FISH OIL SUPPLEMENTATION IN STATIN-TREATED SUBJECTS WITH PERSISTENT HYPERTRIGLYCERIDAEMIA. Vis sammendrag

  Preliminary data indicated that combining fish oil supplementation with statin therapy may enhance the cholesterol-lowering effect of the drug as well as improving plasma triglycerides (Howe et al, Australian Atherosclerosis Society, 1998). We sought to confirm this effect in 45 statin-treated patients with persistent mild hypertriglyceridaemia (avg. 2.2mmol/L) who were randomised to take 4 g/day or 8 g/day of either tuna oil (HiDHA, Clover Corporation) or olive oil (placebo) for 6 months. Plasma lipids were assessed initially and after 3 and 6 months in 40 subjects who completed the trial. As shown in the figure, daily supplementation with 8g of fish oil caused a 27% reduction of plasma triglycerides. Moreover, there was a marginally significant 8% decrease in plasma total cholesterol (TC) with 8g of fish oil, even though TC was already well controlled by the statin therapy (avg 4.5mmol/L). There was no change in TC with the 4g dose. The extent of reduction correlated strongly (r = -0.84) with initial TC levels; the reduction was 13% (p = 0.02) in those subjects (10 per treatment group) with initial TC > 3.8 mmol/L. In this subset, plasma VLDL, IDL and LDL were isolated and assayed for cholesterol and apolipoprotein B. Although not significant, fish oil tended to lower cholesterol and apoB in VLDL and raise both in LDL. There were no significant changes in IDL-cholesterol, IDL-apoB and HDL-cholesterol. In conclusion, a high intake of DHA-rich fish oil can further improve plasma lipids in patients taking statins and may be preferable to drug combinations for treatment of dyslipidaemia.

• Howe, P.R.C.; Hammervold, T.; Meyer, B.; Rustan, Arild & Calvert, G.D. (2001). Omega-3 supplementation improves drug-treatment of hyperlipidaemia. Vis sammendrag

  Preliminary data indicated that adding fish oil to statin therapy may enhance the cholesterol-lowering effect of the drug as well as improving plasma triglycerides (Howe et al, Australian Atherosclerosis Society, 1998). We sought to confirm this effect in 45 statin-treated patients with persistent mild hypertriglyceridaemia (avg. 2.2mM) who were randomised to take a daily dose of 4g or 8g of either DHA-rich tuna oil or placebo (olive oil) for 6 months. Forty subjects completed the trial. Plasma lipids, blood pressure and arterial compliance were assessed initially and after 3 and 6 months. In subjects with initial plasma total cholesterol (TC) >3.8mmol/L, VLDL, IDL, LDL were isolated and assayed for cholesterol and apolipoprotein B. The results showed a significant reduction in plasma triglycerides of 13% by 4g and 27% by 8g fish oil. Even though plasma total cholesterol (TC) was already well controlled by statins (avg 4.5mM), there was a further marginally significant (p = 0.05 compared with placebo) reduction (averaging 8% at 3 and 6 months) with 8g of fish oil. No changes in TC were seen with the 4g dose. As the extent of reduction correlated strongly (r = -0.84) with initial levels, the reduction was 13% (p = 0.02) in those subjects with initial TC>3.8mM. Although not significant, fish oil tended to lower VLDL-cholesterol and VLDL-apoB and raise both in LDL. There were no significant changes in IDL-cholesterol, IDL-apoB and HDL-cholesterol. Thus, fish oil supplementation has the potential to further improve lipids and possibly reduce drug requirements in statin-treated hypercholesterolaemia.

• Rasch-Halvorsen, Mathias; McLennan, Peter & Rustan, Arild (2001). EFFECT OF INDIVIDUAL FATTY ACIDS ON 2-DEOXY-D-GLUCOSE UPTAKE IN CULTURED HUMAN SKELETAL MUSCLE CELLS.
• Aas, Vigdis; Torblå, Siri; Andersen, Merethe H; Jensen, Jørgen & Rustan, Arild (2001). Electrical Stimulation Improves Insulin Responses in a Human Skeletal Muscle Cell Model of Hyperglycemia. Vis sammendrag

  Abstract In order to examine mechanisms involved in insulin resistance, we have established an in vitro model. Myoblasts from human skeletal muscle were isolated from needle biopsy samples of the vastus lateralis of young and healthy volunteers. Contaminating fibroblasts were removed, and myoblasts were fused to differentiated multinucleated myotubes. These myotubes manifested both basal and insulin-stimulated (1-100 nM) glucose transport as well as intracellular glucose metabolism. Insulin increased 2-deoxyglucose uptake 1.4-fold and glycogen synthesis 2.1-fold. Acute electrical stimulation of the myotubes increased 2-deoxyglucoseuptake by about 30 %. Measurements of impedance of cell-covered gold electrodes (ECIS system) showed increased micromotion of caffeine stimulated cells, implying an ability to contract. Treatment with high glucose concentrations for 2-8 days reduced both basal and insulin-stimulated glucose uptake. Maximal effect was seen already after 2 days treatment with 20 mM glucose. Then baseline glucose uptake and glycogen synthesis was reduced by 35 %, insulin stimulated glucose uptake by 25 % and glycogen synthesis by 39 %, respectively. Total cell content of glycogen was not changed by hyperglycemia. The insulin-stimulated glucose uptake in hyperglycemia treated cells was improved by electrical stimulation of the cells. In conclusion, a model of hyperglycemia has been established, and electrical stimulation improved insulin responses.

• Rustan, Arild; Torblå, Siri; Andersen, Merethe H; Jensen, Jørgen; Storlien, Len H. & Aas, Vigdis (2001). HUMAN SKELETAL MUSCLE CELL CULTURES AS A MODEL OF INSULIN RESISTANCE. Vis sammendrag

  Defects in insulin action (insulin resistance) and resultant hyperinsulinemia are strongly linked to the development of type II diabetes (NIDDM) and dyslipidemias. A number of defects in insulin signaling components have been described in insulin resistance. However, it is not clear how these defects appear and how they affect glucose metabolism. Skeletal muscle is the major site of insulin-stimulated glucose metabolism. In order to examine mechanisms involved in insulin resistance, we have established an in vitro cell culture model. Myoblasts were isolated from the vastus lateralis of young healthy volunteers and fused to differentiated multinucleated myotubes. Insulin (0.1-100 nM) increased glucose uptake, glucose oxidation and glycogen synthesis up to 2-fold in these cells. Electrical stimulation of the myotubes increased glucose uptake by about 40%. Measurements of impedance of cell-covered gold electrodes (ECIS system) showed increased micromotion of caffeine stimulated cells, implying an ability to contract. The cells also responded well to insulin at the level of insulin receptor substrate-1 (IRS-1) phosphorylation, activation of phosphoinositide 3-kinase (PI3-K) and protein kinase B (PKB). Preincubation of myotubes with fatty acids (0.6-2 mM oleic and palmitic acid) or high glucose concentration (10-20 mM) induced insulin resistance assessed by decreased glucose uptake, glycogen synthesis and glucose oxidation.

• Rustan, Arild; Andersen, Merethe H; Storlien, Len H.; Berge, Rolf Kristian; Schmitz-Peiffer, Carsten & Aas, Vigdis (2001). FATTY ACID-INDUCED INSULIN RESISTANCE IN HUMAN SKELETAL MUSCLE CELLS. Vis sammendrag

  Skeletal muscle is the major site of insulin-stimulated glucose disposal, and free fatty acids (FFAs) are thought to have diversified effects on muscle insulin action by mechanisms linked to membrane incorporation, increased muscle triacylglycerol storage and increased lipid oxidation. It has also been suggested inhibition of insulin signalling and glucose uptake as well as glycogen synthesis following treatment with fatty acids. Both acute treatment (<4 h) and preincubation (24 h) of myotubes with saturated (palmitate) and monounsaturated (oleate) fatty acids (0.6-2 mM) induced insulin resistance assessed by decreased insulin-stimulated glucose uptake (by 40-60 %), glycogen synthesis (by 20-60 %) and glucose oxidation (by 50%). The mechanism for the acute reduction of glucose utilization by fatty acids was further examined. Tetradecylthioacetic acid (TTA) (a non-b-oxidizable hypolipidemic fatty acid analogue) also decreased glucose oxidation, and etomoxir (a fatty acid oxidation inhibitor) did not prevent the inhibitory effect of fatty acids on glucose oxidation, suggesting no direct substrate competition. Moreover, the fatty acid oleate and TTA did not affect insulin signalling at the level of IRS-1, PI3-K and PKB. At present, we are focusing on how fatty acids affect enzymes and other signalling components involved in glucose and lipid metabolism

• Torblå, Siri; Andersen, Merethe H; Jensen, Jørgen; Rustan, Arild & Aas, Vigdis (2001). HUMAN SKELETAL MUSCLE CELL CULTURES AS A MODEL OF INSULIN RESISTANCE. Vis sammendrag

  Skeletal muscle is the major site of insulin-stimulated glucose metabolism. Defects in insulin action (¿insulin resistance¿) and resultant hyperinsulinemia are strongly linked to the development of a cluster of prevalent diseases, including type II diabetes (NIDDM), obesity, dyslipidemias, hypertension and heart disease. In recent years, a number of defects in insulin signaling components have been described in insulin resistance. However, it is not clear how these defects appear, which are critical and how they affect glucose metabolism. In order to examine mechanisms involved in insulin resistance, we have established an in vitro model. Myoblasts from human skeletal muscle were isolated from needle biopsy samples of the vastus lateralis of young and healthy volunteers. Contaminating fibroblasts were removed, and myoblasts were fused to differentiated multinucleated myotubes. These myotubes manifest both basal and insulin-stimulated (1-1000 nM) glucose transport as well as intracellular glucose metabolism that resemble the in vivo situation. Insulin increased 2-deoxyglucose uptake, glucose oxidation and glycogen synthesis 1.2-2-fold. Acute electrical stimulation of the myotubes increased 2-deoxyglucose-uptake by about 40 %. It was impossible to visually detect contractile activity, but measurements of impedance of cell-covered gold electrodes (ECIS system), showed increased micromotion of caffeine stimulated cells, implying an ability to contract. Contractile activity was confirmed by an increase in glucose oxidation upon electrical stimulation. The cells also responded well to insulin at the level of insulin receptor substrate-1 (IRS-1) phosphorylation, activation of phosphoinositide 3-kinase (PI3-K) and protein kinase B (PKB). Preincubation of myotubes with free fatty acids (0.6-2 mM oleic acid and palmitic acid) or high glucose concentration (10-20 mM) induced ¿insulin resistance¿ assessed by decreased glucose uptake and oxidation. So far the cell system is well characterized and found convenient for investigations on mechanisms involved in different models of insulin resistance. The effect of free fatty acids and high glucose concentration on insulin signaling components will be further studied. In addition, we want to examine if contractile activity can improve insulin sensitivity in this system.

• Andersen, Merethe H; Storlien, Len H.; Aas, Vigdis; Berge, Rolf Kristian; Schmitz-Peiffer, Carsten & Rustan, Arild (2001). Fatty acid-induced insulin resistance in human skeletal muscle cells. Vis sammendrag

  Skeletal muscle is the major site of insulin-stimulated glucose disposal, and free fatty acids (FFAs) are thought to have diversified effects on muscle insulin action by mechanisms linked to membrane incorporation, increased muscle triacylglycerol storage and increased lipid oxidation. It has also been suggested inhibition of insulin signalling and glucose uptake as well as glycogen synthesis following treatment with fatty acids. Both acute treatment (<4 h) and preincubation (24 h) of myotubes with saturated (palmitate) and monounsaturated (oleate) fatty acids (0.6-2 mM) induced insulin resistance assessed by decreased insulin-stimulated glucose uptake (by 40-60 %), glycogen synthesis (by 20-60 %) and glucose oxidation (by 50%). The mechanism for the acute reduction of glucose utilization by fatty acids was further examined. Tetradecylthioacetic acid (a non-b-oxidizable fatty acid analogue) also decreased glucose oxidation, and etomoxir (a fatty acid oxidation inhibitor) did not prevent the inhibitory effect of fatty acids on glucose oxidation, suggesting no direct substrate competition. Moreover, the fatty acid oleate did not affect insulin signalling at the level of IRS-1, PI3-K and PKB. At present, we are focusing on how fatty acids affect enzymes and other signalling components involved in glucose metabolism.

• Rustan, Arild; Torblå, Siri; Andersen, Merethe H; Jensen, Jørgen; Storlien, Len H. & Aas, Vigdis (2001). Human skeletal muscle cell cultures as a model of insulin resistance. Vis sammendrag

  Defects in insulin action (insulin resistance) and resultant hyperinsulinemia are strongly linked to the development of type II diabetes (NIDDM) and dyslipidemias. A number of defects in insulin signaling components have been described in insulin resistance. However, it is not clear how these defects appear and how they affect glucose metabolism. Skeletal muscle is the major site of insulin-stimulated glucose metabolism. In order to examine mechanisms involved in insulin resistance, we have established an in vitro cell culture model. Myoblasts were isolated from the vastus lateralis of young healthy volunteers and fused to differentiated multinucleated myotubes. Insulin (1-1000 nM) increased glucose uptake, glucose oxidation and glycogen synthesis up to 2-fold in these cells. Electrical stimulation of the myotubes increased glucose uptake by about 40%. Measurements of impedance of cell-covered gold electrodes (ECIS system) showed increased micromotion of caffeine stimulated cells, implying an ability to contract. The cells also responded well to insulin at the level of insulin receptor substrate-1 (IRS-1) phosphorylation, activation of phosphoinositide 3-kinase (PI3-K) and protein kinase B (PKB). Preincubation of myotubes with fatty acids (0.6-2 mM oleic and palmitic acid) or high glucose concentration (10-20 mM) induced insulin resistance assessed by decreased glucose uptake and metabolism.

• Rustan, Arild (2000). Lipid-induced insulin resistance in human skeletal muscle primary culture.
• Rustan, Arild (2000). Lipid-induced insulin resistance in human skeletal muscle cells.
• Rustan, Arild (2000). Lipid-induced insulin resistance in human skeletal muscle cells.
• Ukropec, Jozef; Klimes, Ivar; Gasperikova, D.; Reseland, Janne Elin; Drevon, Christian A & Rustan, Arild [Vis alle 7 forfattere av denne artikkelen] (2000). Decreased leptin expression is associated with hypertriglyceridemic effect of fish oil.
• Sebokova, Elena; Ucropec, J.; Reseland, Janne Elin; Rustan, Arild; Drevon, Christian A & Klimes, Ivar (2000). Hypotriglyceridemic effect of n-3 PUFA is associated with decreased leptin expression.
• Sebokova, Elena; Ukropec, Jozef; Rustan, Arild; Reseland, Janne Elin; Drevon, Christian A & Klimes, Ivar (2000). Correction of diet-induced hyperleptinemia and insulin resistance by n-3 PUFAs is associated with increased fatty acid oxidation.
• Berge, Rolf Kristian; Madsen, Lars; Guerre-Millo, Michele; Berge, K.; Bergene, Elin & Flint, E. N. [Vis alle 13 forfattere av denne artikkelen] (2000). Expression of PPARalpha target genes improve insulin action and reduce adiposity.
• Madsen, Lars; Vaagenes, H.; Rustan, Arild & Berge, Rolf Kristian (2000). In contrast to docosahexaenoic acid, eicosapentaenoic acid and hypolipidemic derivatives reduce hepatic synthesis and secretion of triacylglycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation.
• Cazzolli, R.; Rustan, Arild; Biden, T. J. & Schmitz-Peiffer, Carsten (2000). Lipid-induced insulin resistance in human skeletal muscle primary culture.
• Rustan, Arild (1999). Energy transport and fatty acids: with focus on omega-3 fatty acids and the insulin resistance syndrome.
• Rustan, Arild (1999). 3-thia fatty acids. Metabolism and metabolic effects.
• Gedde-Dahl, Ane & Rustan, Arild (1998). Tetradecylthioacetic acid (a 3-thia fatty acid) decreases secretion of newly synthesized, but not preformed, triacylglycerol in CaCo-2 cells.
• Rustan, Arild (1998). Omega-3 and Omega-6 fatty acids in the insulin resistance syndrome (IRS).

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