Skip to main content
SpringerLink
Log in

What Is Lipotoxicity?

  • Chapter
  • First Online:
Obesity and Lipotoxicity

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 960))

Abstract

Enlarged fat cells in obese adipose tissue diminish capacity to store fat and are resistant to the anti-lipolytic effect of insulin. Insulin resistance (IR)-associated S-nitrosylation of insulin-signaling proteins increases in obesity. In accordance with the inhibition of insulin-mediated anti-lipolytic action, plasma free fatty acid (FFA) levels increase. Additionally, endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate/Protein kinase A (cAMP/PKA) and extracellular signal-regulated kinase ½ (ERK1/2) signaling in adipocytes. Failure of packaging of excess lipid into lipid droplets causes chronic elevation of circulating fatty acids, which can reach to toxic levels within non-adipose tissues. Deleterious effects of lipid accumulation in non-adipose tissues are known as lipotoxicity. In fact, triglycerides may also serve a storage function for long-chain non-esterified fatty acids and their products such as ceramides and diacylglycerols (DAGs). Thus, excess DAG, ceramide and saturated fatty acids in obesity can induce chronic inflammation and have harmful effect on multiple organs and systems. In this context, chronic adipose tissue inflammation, mitochondrial dysfunction and IR have been discussed within the scope of lipotoxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abdul-Ghani, M.A., F.L. Muller, Y. Liu, A.O. Chavez, B. Balas, P. Zuo, Z. Chang, D. Tripathy, R. Jani, M. Molina-Carrion, A. Monroy, F. Folli, H. Van Remmen, and R.A. DeFronzo. 2008. Deleterious action of FA metabolites on ATP synthesis: Possible link between lipotoxicity, mitochondrial dysfunction, and insulin resistance. American Journal of Physiology. Endocrinology and Metabolism 295: E678–E685. doi:10.1152/ajpendo.90287.2008.

    Article  CAS  PubMed  Google Scholar 

  • An, J., D.M. Muoio, M. Shiota, Y. Fujimoto, G.W. Cline, G.I. Shulman, T.R. Koves, R. Stevens, D. Millington, and C.B. Newgard. 2004. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nature Medicine 10: 268–274. doi:10.1038/nm995.

    Article  CAS  PubMed  Google Scholar 

  • Angulo, P. 2007. Obesity and nonalcoholic fatty liver disease. Nutrition Reviews 65: S57–S63.

    Article  PubMed  Google Scholar 

  • Aon, M.A., N. Bhatt, and S.C. Cortassa. 2014. Mitochondrial and cellular mechanisms for managing lipid excess. Frontiers in Physiology 5: 282. doi:10.3389/fphys.2014.00282.

    Article  PubMed  PubMed Central  Google Scholar 

  • Belfort, R., L. Mandarino, S. Kashyap, K. Wirfel, T. Pratipanawatr, R. Berria, R.A. Defronzo, and K. Cusi. 2005. Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 54: 1640–1648.

    Article  CAS  PubMed  Google Scholar 

  • Bellini, L., M. Campana, R. Mahfouz, A. Carlier, J. Véret, C. Magnan, E. Hajduch, and H. Le Stunff. 2015. Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes. Expert Opinion on Therapeutic Targets 19: 1037–1050. doi:10.1517/14728222.2015.1028359.

    Article  CAS  PubMed  Google Scholar 

  • Boden, G. 2008. Obesity and free fatty acids. Endocrinology and Metabolism Clinics of North America 37: 635–646 . doi:10.1016/j.ecl.2008.06.007. viii–ix

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boden, G., and X. Chen. 1995. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. The Journal of Clinical Investigation 96: 1261–1268. doi:10.1172/JCI118160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boden, G., P. She, M. Mozzoli, P. Cheung, K. Gumireddy, P. Reddy, X. Xiang, Z. Luo, and N. Ruderman. 2005. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes 54: 3458–3465.

    Article  CAS  PubMed  Google Scholar 

  • Bonen, A., J.J. Luiken, Y. Arumugam, J.F. Glatz, and N.N. Tandon. 2000. Acute regulation of fatty acid uptake involves the cellular redistribution of fatty acid translocase. The Journal of Biological Chemistry 275: 14501–14508.

    Article  CAS  PubMed  Google Scholar 

  • Bonen, A., M.L. Parolin, G.R. Steinberg, J. Calles-Escandon, N.N. Tandon, J.F.C. Glatz, J.J.F.P. Luiken, G.J.F. Heigenhauser, and D.J. Dyck. 2004. Triacylglycerol accumulation in human obesity and type 2 diabetes is associated with increased rates of skeletal muscle fatty acid transport and increased sarcolemmal FAT/CD36. FASEB Journal 18: 1144–1146. doi:10.1096/fj.03-1065fje.

    CAS  PubMed  Google Scholar 

  • Borradaile, N.M., X. Han, J.D. Harp, S.E. Gale, D.S. Ory, and J.E. Schaffer. 2006. Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. Journal of Lipid Research 47: 2726–2737. doi:10.1194/jlr.M600299-JLR200.

    Article  CAS  PubMed  Google Scholar 

  • Bosma, M., D.H. Dapito, Z. Drosatos-Tampakaki, N. Huiping-Son, L.-S. Huang, S. Kersten, K. Drosatos, and I.J. Goldberg. 2014. Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity. Biochimica et Biophysica Acta 1841: 1648–1655. doi:10.1016/j.bbalip.2014.09.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brand, M.D., and T.C. Esteves. 2005. Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metabolism 2: 85–93. doi:10.1016/j.cmet.2005.06.002.

    Article  CAS  PubMed  Google Scholar 

  • Brasaemle, D.L. 2007. Thematic review series: Adipocyte biology. The perilipin family of structural lipid droplet proteins: Stabilization of lipid droplets and control of lipolysis. Journal of Lipid Research 48: 2547–2559. doi:10.1194/jlr.R700014-JLR200.

    Article  CAS  PubMed  Google Scholar 

  • Brookheart, R.T., C.I. Michel, and J.E. Schaffer. 2009. As a matter of fat. Cell Metabolism 10: 9–12. doi:10.1016/j.cmet.2009.03.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown, M.S., and J.L. Goldstein. 1997. The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89: 331–340.

    Article  CAS  PubMed  Google Scholar 

  • ———. 2009. Cholesterol feedback: From Schoenheimer’s bottle to Scap’s MELADL. Journal of Lipid Research 50(Suppl): S15–S27. doi:10.1194/jlr.R800054-JLR200.

    PubMed  PubMed Central  Google Scholar 

  • Cai, D., M. Yuan, D.F. Frantz, P.A. Melendez, L. Hansen, J. Lee, and S.E. Shoelson. 2005. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nature Medicine 11: 183–190. doi:10.1038/nm1166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell, F.M., R. Kozak, A. Wagner, J.Y. Altarejos, J.R.B. Dyck, D.D. Belke, D.L. Severson, D.P. Kelly, and G.D. Lopaschuk. 2002. A role for peroxisome proliferator-activated receptor alpha (PPARalpha) in the control of cardiac malonyl-CoA levels: Reduced fatty acid oxidation rates and increased glucose oxidation rates in the hearts of mice lacking PPARalpha are associated with higher concentrations of malonyl-CoA and reduced expression of malonyl-CoA decarboxylase. The Journal of Biological Chemistry 277: 4098–4103. doi:10.1074/jbc.M106054200.

    Article  CAS  PubMed  Google Scholar 

  • Campbell, S.E., N.N. Tandon, G. Woldegiorgis, J.J.F.P. Luiken, J.F.C. Glatz, and A. Bonen. 2004. A novel function for fatty acid translocase (FAT)/CD36: Involvement in long chain fatty acid transfer into the mitochondria. The Journal of Biological Chemistry 279: 36235–36241. doi:10.1074/jbc.M400566200.

    Article  CAS  PubMed  Google Scholar 

  • Carobbio, S., R.M. Hagen, C.J. Lelliott, M. Slawik, G. Medina-Gomez, C.-Y. Tan, A. Sicard, H.J. Atherton, N. Barbarroja, M. Bjursell, M. Bohlooly-Y, S. Virtue, A. Tuthill, E. Lefai, M. Laville, T. Wu, R.V. Considine, H. Vidal, D. Langin, M. Oresic, F.J. Tinahones, J.M. Fernandez-Real, J.L. Griffin, J.K. Sethi, M. López, and A. Vidal-Puig. 2013. Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity. Diabetes 62: 3697–3708. doi:10.2337/db12-1748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carpentier, A., S.D. Mittelman, R.N. Bergman, A. Giacca, and G.F. Lewis. 2000. Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes. Diabetes 49: 399–408.

    Article  CAS  PubMed  Google Scholar 

  • Chabowski, A., S.L.M. Coort, J. Calles-Escandon, N.N. Tandon, J.F.C. Glatz, J.J.F.P. Luiken, and A. Bonen. 2004. Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm. American Journal of Physiology. Endocrinology and Metabolism 287: E781–E789. doi:10.1152/ajpendo.00573.2003.

    Article  CAS  PubMed  Google Scholar 

  • Chabowski, A., J. Górski, J.J.F.P. Luiken, J.F.C. Glatz, and A. Bonen. 2007. Evidence for concerted action of FAT/CD36 and FABPpm to increase fatty acid transport across the plasma membrane. Prostaglandins Leukot Essent Fatty Acids 77: 345–353.

    Article  CAS  PubMed  Google Scholar 

  • Chavez, J.A., T.A. Knotts, L.-P. Wang, G. Li, R.T. Dobrowsky, G.L. Florant, and S.A. Summers. 2003. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. The Journal of Biological Chemistry 278: 10297–10303. doi:10.1074/jbc.M212307200.

    Article  CAS  PubMed  Google Scholar 

  • Civelek, V.N., J.A. Hamilton, K. Tornheim, K.L. Kelly, and B.E. Corkey. 1996. Intracellular pH in adipocytes: Effects of free fatty acid diffusion across the plasma membrane, lipolytic agonists, and insulin. Proceedings of the National Academy of Sciences of the United States of America 93: 10139–10144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clarke, D.C., D. Miskovic, X.-X. Han, J. Calles-Escandon, J.F.C. Glatz, J.J.F.P. Luiken, J.J. Heikkila, and A. Bonen. 2004. Overexpression of membrane-associated fatty acid binding protein (FABPpm) in vivo increases fatty acid sarcolemmal transport and metabolism. Physiological Genomics 17: 31–37. doi:10.1152/physiolgenomics.00190.2003.

    Article  CAS  PubMed  Google Scholar 

  • Cooney, G.J., A.L. Thompson, S.M. Furler, J. Ye, and E.W. Kraegen. 2002. Muscle long-chain acyl CoA esters and insulin resistance. Annals of the New York Academy of Sciences 967: 196–207.

    Article  CAS  PubMed  Google Scholar 

  • Copps, K.D., and M.F. White. 2012. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55: 2565–2582. doi:10.1007/s00125-012-2644-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Creager, M.A., T.F. Lüscher, F. Cosentino, and J.A. Beckman. 2003. Diabetes and vascular disease: Pathophysiology, clinical consequences, and medical therapy: Part I. Circulation 108: 1527–1532. doi:10.1161/01.CIR.0000091257.27563.32.

    Article  PubMed  Google Scholar 

  • Crompton, M. 1999. The mitochondrial permeability transition pore and its role in cell death. The Biochemical Journal 341(Pt 2): 233–249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DeFronzo, R.A. 2004. Dysfunctional fat cells, lipotoxicity and type 2 diabetes. International Journal of Clinical Practice Supplement: 9–21.

    Google Scholar 

  • Deng, J., S. Liu, L. Zou, C. Xu, B. Geng, and G. Xu. 2012. Lipolysis response to endoplasmic reticulum stress in adipose cells. The Journal of Biological Chemistry 287: 6240–6249. doi:10.1074/jbc.M111.299115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diehl, A.M. 2002. Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines. American Journal of Physiology. Gastrointestinal and Liver Physiology 282: G1–G5. doi:10.1152/ajpgi.00384.2001.

    Article  CAS  PubMed  Google Scholar 

  • Digel, M., R. Ehehalt, W. Stremmel, and J. Füllekrug. 2009. Acyl-CoA synthetases: Fatty acid uptake and metabolic channeling. Molecular and Cellular Biochemistry 326: 23–28. doi:10.1007/s11010-008-0003-3.

    Article  CAS  PubMed  Google Scholar 

  • Divakaruni, A.S., and M.D. Brand. 2011. The regulation and physiology of mitochondrial proton leak. Physiology (Bethesda) 26: 192–205. doi:10.1152/physiol.00046.2010.

    Article  CAS  Google Scholar 

  • Divakaruni, A.S., D.M. Humphrey, and M.D. Brand. 2012. Fatty acids change the conformation of uncoupling protein 1 (UCP1). The Journal of Biological Chemistry 287: 36845–36853. doi:10.1074/jbc.M112.381780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dresner, A., D. Laurent, M. Marcucci, M.E. Griffin, S. Dufour, G.W. Cline, L.A. Slezak, D.K. Andersen, R.S. Hundal, D.L. Rothman, K.F. Petersen, and G.I. Shulman. 1999. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. The Journal of Clinical Investigation 103: 253–259. doi:10.1172/JCI5001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Egnatchik, R.A., A.K. Leamy, Y. Noguchi, M. Shiota, and J.D. Young. 2014. Palmitate-induced activation of mitochondrial metabolism promotes oxidative stress and apoptosis in H4IIEC3 rat hepatocytes. Metabolism 63: 283–295. doi:10.1016/j.metabol.2013.10.009.

    Article  CAS  PubMed  Google Scholar 

  • Elam, M.B., C. Yellaturu, G.E. Howell, X. Deng, G.S. Cowan, P. Kumar, E.A. Park, M.L. Hiler, H.G. Wilcox, T.A. Hughes, G.A. Cook, and R. Raghow. 2010. Dysregulation of sterol regulatory element binding protein-1c in livers of morbidly obese women is associated with altered suppressor of cytokine signaling-3 and signal transducer and activator of transcription-1 signaling. Metabolism 59: 587–598. doi:10.1016/j.metabol.2009.09.001.

    Article  CAS  PubMed  Google Scholar 

  • Emanuelli, B., P. Peraldi, C. Filloux, C. Chavey, K. Freidinger, D.J. Hilton, G.S. Hotamisligil, and E. Van Obberghen. 2001. SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. The Journal of Biological Chemistry 276: 47944–47949. doi:10.1074/jbc.M104602200.

    Article  CAS  PubMed  Google Scholar 

  • Erikci Ertunc, M., and G.S. Hotamisligil. 2016. Lipid signaling and lipotoxicity in metabolic inflammation: Indications for metabolic disease pathogenesis and treatment. Journal of Lipid Research. doi:10.1194/jlr.R066514.

    Google Scholar 

  • Espinosa, A., A. García, S. Härtel, C. Hidalgo, and E. Jaimovich. 2009. NADPH oxidase and hydrogen peroxide mediate insulin-induced calcium increase in skeletal muscle cells. The Journal of Biological Chemistry 284: 2568–2575. doi:10.1074/jbc.M804249200.

    Article  CAS  PubMed  Google Scholar 

  • Esser, N., S. Legrand-Poels, J. Piette, A.J. Scheen, and N. Paquot. 2014. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Research and Clinical Practice 105: 141–150. doi:10.1016/j.diabres.2014.04.006.

    Article  CAS  PubMed  Google Scholar 

  • Fang, X., R. Palanivel, J. Cresser, K. Schram, R. Ganguly, F.S.L. Thong, J. Tuinei, A. Xu, E.D. Abel, and G. Sweeney. 2010. An APPL1-AMPK signaling axis mediates beneficial metabolic effects of adiponectin in the heart. American Journal of Physiology. Endocrinology and Metabolism 299: E721–E729. doi:10.1152/ajpendo.00086.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallardo, N., E. Bonzón-Kulichenko, T. Fernández-Agulló, E. Moltó, S. Gómez-Alonso, P. Blanco, J.M. Carrascosa, M. Ros, and A. Andrés. 2007. Tissue-specific effects of central leptin on the expression of genes involved in lipid metabolism in liver and white adipose tissue. Endocrinology 148: 5604–5610. doi:10.1210/en.2007-0933.

    Article  CAS  PubMed  Google Scholar 

  • Gao, X., K. Li, X. Hui, X. Kong, G. Sweeney, Y. Wang, A. Xu, M. Teng, P. Liu, and D. Wu. 2011. Carnitine palmitoyltransferase 1A prevents fatty acid-induced adipocyte dysfunction through suppression of c-Jun N-terminal kinase. The Biochemical Journal 435: 723–732. doi:10.1042/BJ20101680.

    Article  CAS  PubMed  Google Scholar 

  • Garin-Shkolnik, T., A. Rudich, G.S. Hotamisligil, and M. Rubinstein. 2014. FABP4 attenuates PPARγ and adipogenesis and is inversely correlated with PPARγ in adipose tissues. Diabetes 63: 900–911. doi:10.2337/db13-0436.

    Article  CAS  PubMed  Google Scholar 

  • Garland, P.B., P.J. Randle, and E.A. Newsholme. 1963. Citrate as an intermediary in the inhibition of phosphofructokinase in rat heart muscle by fatty acids, ketone bodies, pyruvate, diabetes, and starvation. Nature 200: 169–170.

    Article  CAS  PubMed  Google Scholar 

  • Goglia, F., and V.P. Skulachev. 2003. A function for novel uncoupling proteins: Antioxidant defense of mitochondrial matrix by translocating fatty acid peroxides from the inner to the outer membrane leaflet. FASEB Journal 17: 1585–1591. doi:10.1096/fj.03-0159hyp.

    Article  CAS  PubMed  Google Scholar 

  • Hajduch, E., A. Balendran, I.H. Batty, G.J. Litherland, A.S. Blair, C.P. Downes, and H.S. Hundal. 2001. Ceramide impairs the insulin-dependent membrane recruitment of protein kinase B leading to a loss in downstream signalling in L6 skeletal muscle cells. Diabetologia 44: 173–183. doi:10.1007/s001250051596.

    Article  CAS  PubMed  Google Scholar 

  • Hegarty, B.D., S.M. Furler, J. Ye, G.J. Cooney, and E.W. Kraegen. 2003. The role of intramuscular lipid in insulin resistance. Acta Physiologica Scandinavica 178: 373–383. doi:10.1046/j.1365-201X.2003.01162.x.

    Article  CAS  PubMed  Google Scholar 

  • Heilbronn, L., S.R. Smith, and E. Ravussin. 2004. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. International Journal of Obesity 28(Suppl 4): S12–S21. doi:10.1038/sj.ijo.0802853.

    Article  CAS  PubMed  Google Scholar 

  • van Herpen, N.A., and V.B. Schrauwen-Hinderling. 2008. Lipid accumulation in non-adipose tissue and lipotoxicity. Physiology & Behavior 94: 231–241. doi:10.1016/j.physbeh.2007.11.049.

    Article  CAS  Google Scholar 

  • Hirabara, S.M., R. Curi, P. Maechler. 2010. Saturated fatty acid-induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cells. Journal of Cellular Physiology 222: 187–194. doi:10.1002/jcp.21936

    Google Scholar 

  • Hoeks, J., M.K.C. Hesselink, and P. Schrauwen. 2006. Involvement of UCP3 in mild uncoupling and lipotoxicity. Experimental Gerontology 41: 658–662. doi:10.1016/j.exger.2006.02.005.

    Article  CAS  PubMed  Google Scholar 

  • Holland, W.L., J.T. Brozinick, L.-P. Wang, E.D. Hawkins, K.M. Sargent, Y. Liu, K. Narra, K.L. Hoehn, T.A. Knotts, A. Siesky, D.H. Nelson, S.K. Karathanasis, G.K. Fontenot, M.J. Birnbaum, and S.A. Summers. 2007. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metabolism 5: 167–179. doi:10.1016/j.cmet.2007.01.002.

    Article  CAS  PubMed  Google Scholar 

  • Holloway, G.P., A. Bonen, and L.L. Spriet. 2009. Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals. The American Journal of Clinical Nutrition 89: 455S–462S. doi:10.3945/ajcn.2008.26717B.

    Article  CAS  PubMed  Google Scholar 

  • Holloway, G.P., J. Lally, J.G. Nickerson, H. Alkhateeb, L.A. Snook, G.J.F. Heigenhauser, J. Calles-Escandon, J.F.C. Glatz, J.J.F.P. Luiken, L.L. Spriet, and A. Bonen. 2007. Fatty acid binding protein facilitates sarcolemmal fatty acid transport but not mitochondrial oxidation in rat and human skeletal muscle. The Journal of Physiology 582: 393–405. doi:10.1113/jphysiol.2007.135301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horton, J.D., J.L. Goldstein, and M.S. Brown. 2002. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. The Journal of Clinical Investigation 109: 1125–1131. doi:10.1172/JCI15593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hotamisligil, G.S. 2005. Role of endoplasmic reticulum stress and c-Jun NH2-terminal kinase pathways in inflammation and origin of obesity and diabetes. Diabetes 54(Suppl 2): S73–S78.

    Article  CAS  PubMed  Google Scholar 

  • Hue, L., and H. Taegtmeyer. 2009. The Randle cycle revisited: A new head for an old hat. American Journal of Physiology. Endocrinology and Metabolism 297: E578–E591. doi:10.1152/ajpendo.00093.2009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Inoguchi, T., P. Li, F. Umeda, H.Y. Yu, M. Kakimoto, M. Imamura, T. Aoki, T. Etoh, T. Hashimoto, M. Naruse, H. Sano, H. Utsumi, and H. Nawata. 2000. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 49: 1939–1945.

    Article  CAS  PubMed  Google Scholar 

  • Ishii, M., A. Maeda, S. Tani, and M. Akagawa. 2015. Palmitate induces insulin resistance in human HepG2 hepatocytes by enhancing ubiquitination and proteasomal degradation of key insulin signaling molecules. Archives of Biochemistry and Biophysics 566: 26–35. doi:10.1016/j.abb.2014.12.009.

    Article  CAS  PubMed  Google Scholar 

  • Jacob, S. 1987. Lipid droplet accumulation in the heart during fasting. Acta Histochemica 82: 149–152. doi:10.1016/S0065-1281(87)80020-X.

    Article  CAS  PubMed  Google Scholar 

  • Jaishy, B., Q. Zhang, H.S. Chung, C. Riehle, J. Soto, S. Jenkins, P. Abel, L.A. Cowart, J.E. Van Eyk, and E.D. Abel. 2015. Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. Journal of Lipid Research 56: 546–561. doi:10.1194/jlr.M055152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaiswal, A.K. 2004. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radical Biology & Medicine 36: 1199–1207. doi:10.1016/j.freeradbiomed.2004.02.074.

    Article  CAS  Google Scholar 

  • Jensen, M.D., M.W. Haymond, R.A. Rizza, P.E. Cryer, and J.M. Miles. 1989. Influence of body fat distribution on free fatty acid metabolism in obesity. The Journal of Clinical Investigation 83: 1168–1173. doi:10.1172/JCI113997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kelley, D.E., and J.A. Simoneau. 1994. Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus. The Journal of Clinical Investigation 94: 2349–2356. doi:10.1172/JCI117600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kerner, J., and C. Hoppel. 2000. Fatty acid import into mitochondria. Biochimica et Biophysica Acta 1486: 1–17.

    Article  CAS  PubMed  Google Scholar 

  • Koonen, D.P.Y., J.F.C. Glatz, A. Bonen, and J.J.F.P. Luiken. 2005. Long-chain fatty acid uptake and FAT/CD36 translocation in heart and skeletal muscle. Biochimica et Biophysica Acta 1736: 163–180. doi:10.1016/j.bbalip.2005.08.018.

    Article  CAS  PubMed  Google Scholar 

  • Korshunov, S.S., O.V. Korkina, E.K. Ruuge, V.P. Skulachev, and A.A. Starkov. 1998. Fatty acids as natural uncouplers preventing generation of O2.- and H2O2 by mitochondria in the resting state. FEBS Letters 435: 215–218.

    Article  CAS  PubMed  Google Scholar 

  • Koutsari, C., and M.D. Jensen. 2006. Thematic review series: Patient-oriented research. Free fatty acid metabolism in human obesity. Journal of Lipid Research 47: 1643–1650. doi:10.1194/jlr.R600011-JLR200.

    Article  CAS  PubMed  Google Scholar 

  • Koves, T.R., J.R. Ussher, R.C. Noland, D. Slentz, M. Mosedale, O. Ilkayeva, J. Bain, R. Stevens, J.R.B. Dyck, C.B. Newgard, G.D. Lopaschuk, and D.M. Muoio. 2008. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metabolism 7: 45–56. doi:10.1016/j.cmet.2007.10.013.

    Article  CAS  PubMed  Google Scholar 

  • Kovsan, J., R. Ben-Romano, S.C. Souza, A.S. Greenberg, and A. Rudich. 2007. Regulation of adipocyte lipolysis by degradation of the perilipin protein: Nelfinavir enhances lysosome-mediated perilipin proteolysis. The Journal of Biological Chemistry 282: 21704–21711. doi:10.1074/jbc.M702223200.

    Article  CAS  PubMed  Google Scholar 

  • Kroemer, G., L. Galluzzi, and C. Brenner. 2007. Mitochondrial membrane permeabilization in cell death. Physiological Reviews 87: 99–163. doi:10.1152/physrev.00013.2006.

    Article  CAS  PubMed  Google Scholar 

  • Kuramoto, K., T. Okamura, T. Yamaguchi, T.Y. Nakamura, S. Wakabayashi, H. Morinaga, M. Nomura, T. Yanase, K. Otsu, N. Usuda, S. Matsumura, K. Inoue, T. Fushiki, Y. Kojima, T. Hashimoto, F. Sakai, F. Hirose, and T. Osumi. 2012. Perilipin 5, a lipid droplet-binding protein, protects heart from oxidative burden by sequestering fatty acid from excessive oxidation. The Journal of Biological Chemistry 287: 23852–23863. doi:10.1074/jbc.M111.328708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kusminski, C.M., S. Shetty, L. Orci, R.H. Unger, and P.E. Scherer. 2009. Diabetes and apoptosis: Lipotoxicity. Apoptosis 14: 1484–1495. doi:10.1007/s10495-009-0352-8.

    Article  CAS  PubMed  Google Scholar 

  • Lam, Y.Y., G. Hatzinikolas, J.M. Weir, A. Janovská, A.J. McAinch, P. Game, P.J. Meikle, and G.A. Wittert. 2011. Insulin-stimulated glucose uptake and pathways regulating energy metabolism in skeletal muscle cells: The effects of subcutaneous and visceral fat, and long-chain saturated, n-3 and n-6 polyunsaturated fatty acids. Biochimica et Biophysica Acta 1811: 468–475. doi:10.1016/j.bbalip.2011.04.011.

    Article  CAS  PubMed  Google Scholar 

  • Las, G., and O.S. Shirihai. 2010. The role of autophagy in β-cell lipotoxicity and type 2 diabetes. Diabetes, Obesity & Metabolism 12(Suppl 2): 15–19. doi:10.1111/j.1463-1326.2010.01268.x.

    Article  CAS  Google Scholar 

  • Las, G., S.B. Serada, J.D. Wikstrom, G. Twig, and O.S. Shirihai. 2011. Fatty acids suppress autophagic turnover in β-cells. The Journal of Biological Chemistry 286: 42534–42544. doi:10.1074/jbc.M111.242412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Le Marchand-Brustel, Y., P. Gual, T. Grémeaux, T. Gonzalez, R. Barrès, and J.-F. Tanti. 2003. Fatty acid-induced insulin resistance: Role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling. Biochemical Society Transactions 31: 1152–1156.

    Article  CAS  PubMed  Google Scholar 

  • Li, R., H. Guan, and K. Yang. 2012. Neuropeptide Y potentiates beta-adrenergic stimulation of lipolysis in 3 T3-L1 adipocytes. Regulatory Peptides 178: 16–20. doi:10.1016/j.regpep.2012.06.002.

    Article  CAS  PubMed  Google Scholar 

  • Listenberger, L.L., and J.E. Schaffer. 2002. Mechanisms of lipoapoptosis: Implications for human heart disease. Trends in Cardiovascular Medicine 12: 134–138.

    Article  CAS  PubMed  Google Scholar 

  • Listenberger, L.L., X. Han, S.E. Lewis, S. Cases, R.V. Farese, D.S. Ory, and J.E. Schaffer. 2003. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proceedings of the National Academy of Sciences of the United States of America 100: 3077–3082. doi:10.1073/pnas.0630588100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Listenberger, L.L., D.S. Ory, and J.E. Schaffer. 2001. Palmitate-induced apoptosis can occur through a ceramide-independent pathway. The Journal of Biological Chemistry 276: 14890–14895. doi:10.1074/jbc.M010286200.

    Article  CAS  PubMed  Google Scholar 

  • Londos, C., D.L. Brasaemle, C.J. Schultz, D.C. Adler-Wailes, D.M. Levin, A.R. Kimmel, and C.M. Rondinone. 1999a. On the control of lipolysis in adipocytes. Annals of the New York Academy of Sciences 892: 155–168.

    Article  CAS  PubMed  Google Scholar 

  • Londos, C., D.L. Brasaemle, C.J. Schultz, J.P. Segrest, and A.R. Kimmel. 1999b. Perilipins, ADRP, and other proteins that associate with intracellular neutral lipid droplets in animal cells. Seminars in Cell & Developmental Biology 10: 51–58. doi:10.1006/scdb.1998.0275.

    Article  CAS  Google Scholar 

  • van Loon, L.J.C., and B.H. Goodpaster. 2006. Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state. Pflügers Archiv 451: 606–616. doi:10.1007/s00424-005-1509-0.

    Article  CAS  PubMed  Google Scholar 

  • Lowell, B.B., and G.I. Shulman. 2005. Mitochondrial dysfunction and type 2 diabetes. Science 307: 384–387. doi:10.1126/science.1104343.

    Article  CAS  PubMed  Google Scholar 

  • de Luca, C., and J.M. Olefsky. 2008. Inflammation and insulin resistance. FEBS Letters 582: 97–105. doi:10.1016/j.febslet.2007.11.057.

    Article  PubMed  CAS  Google Scholar 

  • Mailloux, R.J., E.L. Seifert, F. Bouillaud, C. Aguer, S. Collins, and M.-E. Harper. 2011. Glutathionylation acts as a control switch for uncoupling proteins UCP2 and UCP3. The Journal of Biological Chemistry 286: 21865–21875. doi:10.1074/jbc.M111.240242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGarry, J.D. 2002. Banting lecture 2001: Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51: 7–18.

    Article  CAS  PubMed  Google Scholar 

  • McGarry, J.D., G.P. Mannaerts, and D.W. Foster. 1977. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. The Journal of Clinical Investigation 60: 265–270. doi:10.1172/JCI108764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Medina-Gomez, G., S. Gray, and A. Vidal-Puig. 2007. Adipogenesis and lipotoxicity: Role of peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgammacoactivator-1 (PGC1). Public Health Nutrition 10: 1132–1137. doi:10.1017/S1368980007000614.

    Article  PubMed  Google Scholar 

  • Mei, S., H.-M. Ni, S. Manley, A. Bockus, K.M. Kassel, J.P. Luyendyk, B.L. Copple, and W.-X. Ding. 2011. Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. The Journal of Pharmacology and Experimental Therapeutics 339: 487–498. doi:10.1124/jpet.111.184341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minokoshi, Y., Y.-B. Kim, O.D. Peroni, L.G.D. Fryer, C. Müller, D. Carling, and B.B. Kahn. 2002. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415: 339–343. doi:10.1038/415339a.

    Article  CAS  PubMed  Google Scholar 

  • Miyoshi, H., S.C. Souza, H.-H. Zhang, K.J. Strissel, M.A. Christoffolete, J. Kovsan, A. Rudich, F.B. Kraemer, A.C. Bianco, M.S. Obin, and A.S. Greenberg. 2006. Perilipin promotes hormone-sensitive lipase-mediated adipocyte lipolysis via phosphorylation-dependent and -independent mechanisms. The Journal of Biological Chemistry 281: 15837–15844. doi:10.1074/jbc.M601097200.

    Article  CAS  PubMed  Google Scholar 

  • Möhlig, M., F. Isken, M. Ristow. 2004. Impaired mitochondrial activity and insulin-resistant offspring of patients with type 2 diabetes. The New England Journal of Medicine 350: 2419–2421-2421.

    Google Scholar 

  • Monsénégo, J., A. Mansouri, M. Akkaoui, V. Lenoir, C. Esnous, V. Fauveau, V. Tavernier, J. Girard, and C. Prip-Buus. 2012. Enhancing liver mitochondrial fatty acid oxidation capacity in obese mice improves insulin sensitivity independently of hepatic steatosis. Journal of Hepatology 56: 632–639. doi:10.1016/j.jhep.2011.10.008.

    Article  PubMed  CAS  Google Scholar 

  • Montell, E., M. Turini, M. Marotta, M. Roberts, V. Noé, C.J. Ciudad, K. Macé, and A.M. Gómez-Foix. 2001. DAG accumulation from saturated fatty acids desensitizes insulin stimulation of glucose uptake in muscle cells. American Journal of Physiology. Endocrinology and Metabolism 280: E229–E237.

    CAS  PubMed  Google Scholar 

  • Moon, Y.-A., G. Liang, X. Xie, M. Frank-Kamenetsky, K. Fitzgerald, V. Koteliansky, M.S. Brown, J.L. Goldstein, and J.D. Horton. 2012. The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate-induced hypertriglyceridemia in animals. Cell Metabolism 15: 240–246. doi:10.1016/j.cmet.2011.12.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morino, K., K.F. Petersen, and G.I. Shulman. 2006. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55(Suppl 2): S9–S15. doi:10.2337/db06-S002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muoio, D.M., and P.D. Neufer. 2012. Lipid-induced mitochondrial stress and insulin action in muscle. Cell Metabolism 15: 595–605. doi:10.1016/j.cmet.2012.04.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagle, C.A., E.L. Klett, and R.A. Coleman. 2009. Hepatic triacylglycerol accumulation and insulin resistance. Journal of Lipid Research 50(Suppl): S74–S79. doi:10.1194/jlr.R800053-JLR200.

    PubMed  PubMed Central  Google Scholar 

  • Nakamura, M.T., B.E. Yudell, and J.J. Loor. 2014. Regulation of energy metabolism by long-chain fatty acids. Progress in Lipid Research 53: 124–144. doi:10.1016/j.plipres.2013.12.001.

    Article  CAS  PubMed  Google Scholar 

  • Nielsen, T.S., N. Jessen, J.O.L. Jørgensen, N. Møller, and S. Lund. 2014. Dissecting adipose tissue lipolysis: Molecular regulation and implications for metabolic disease. Journal of Molecular Endocrinology 52: R199–R222. doi:10.1530/JME-13-0277.

    Article  CAS  PubMed  Google Scholar 

  • Noguchi, Y., J.D. Young, J.O. Aleman, M.E. Hansen, J.K. Kelleher, and G. Stephanopoulos. 2009. Effect of anaplerotic fluxes and amino acid availability on hepatic lipoapoptosis. The Journal of Biological Chemistry 284: 33425–33436. doi:10.1074/jbc.M109.049478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nolan, C.J., and C.Z. Larter. 2009. Lipotoxicity: Why do saturated fatty acids cause and monounsaturates protect against it? Journal of Gastroenterology and Hepatology 24: 703–706. doi:10.1111/j.1440-1746.2009.05823.x.

    Article  CAS  PubMed  Google Scholar 

  • Okumura, T., K. Harada, K. Oue, J. Zhang, S. Asano, M. Hayashiuchi, A. Mizokami, H. Tanaka, M. Irifune, N. Kamata, M. Hirata, and T. Kanematsu. 2014. Phospholipase C-related catalytically inactive protein (PRIP) regulates lipolysis in adipose tissue by modulating the phosphorylation of hormone-sensitive lipase. PLoS One 9: e100559. doi:10.1371/journal.pone.0100559.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ozcan, U., Q. Cao, E. Yilmaz, A.-H. Lee, N.N. Iwakoshi, E. Ozdelen, G. Tuncman, C. Görgün, L.H. Glimcher, and G.S. Hotamisligil. 2004. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306: 457–461. doi:10.1126/science.1103160.

    Article  PubMed  CAS  Google Scholar 

  • Paz, K., R. Hemi, D. LeRoith, A. Karasik, E. Elhanany, H. Kanety, and Y. Zick. 1997. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. The Journal of Biological Chemistry 272: 29911–29918.

    Article  CAS  PubMed  Google Scholar 

  • Pederson, T.M., D.L. Kramer, and C.M. Rondinone. 2001. Serine/threonine phosphorylation of IRS-1 triggers its degradation: Possible regulation by tyrosine phosphorylation. Diabetes 50: 24–31.

    Article  CAS  PubMed  Google Scholar 

  • Petersen, K.F., D. Befroy, S. Dufour, J. Dziura, C. Ariyan, D.L. Rothman, L. DiPietro, G.W. Cline, and G.I. Shulman. 2003. Mitochondrial dysfunction in the elderly: Possible role in insulin resistance. Science 300: 1140–1142. doi:10.1126/science.1082889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Phielix, E., T. Jelenik, P. Nowotny, J. Szendroedi, and M. Roden. 2014. Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: A randomised clinical trial. Diabetologia 57: 572–581. doi:10.1007/s00125-013-3127-2.

    Article  CAS  PubMed  Google Scholar 

  • Quan, W., H.S. Jung, and M.-S. Lee. 2013. Role of autophagy in the progression from obesity to diabetes and in the control of energy balance. Archives of Pharmacal Research 36: 223–229. doi:10.1007/s12272-013-0024-7.

    Article  CAS  PubMed  Google Scholar 

  • Quan, W., Y.M. Lim, and M.S. Lee. 2012. Role of autophagy in diabetes and endoplasmic reticulum stress of pancreatic β-cells. Experimental & Molecular Medicine 44: 81–88. doi:10.3858/emm.2012.44.2.030.

    Article  CAS  Google Scholar 

  • Ratner, C., A.N. Madsen, L.V. Kristensen, L.J. Skov, K.S. Pedersen, O.H. Mortensen, G.M. Knudsen, K. Raun, and B. Holst. 2015. Impaired oxidative capacity due to decreased CPT1b levels as a contributing factor to fat accumulation in obesity. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 308: R973–R982. doi:10.1152/ajpregu.00219.2014.

    Article  CAS  PubMed  Google Scholar 

  • Reuter, S.E., and A.M. Evans. 2012. Carnitine and acylcarnitines: Pharmacokinetic, pharmacological and clinical aspects. Clinical Pharmacokinetics 51: 553–572. doi:10.2165/11633940-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  • Rial, E., L. Rodríguez-Sánchez, E. Gallardo-Vara, P. Zaragoza, E. Moyano, and M.M. González-Barroso. 2010. Lipotoxicity, fatty acid uncoupling and mitochondrial carrier function. Biochimica et Biophysica Acta 1797: 800–806. doi:10.1016/j.bbabio.2010.04.001.

    Article  CAS  PubMed  Google Scholar 

  • Rindler, P.M., C.L. Crewe, J. Fernandes, M. Kinter, and L.I. Szweda. 2013a. Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria. American Journal of Physiology. Heart and Circulatory Physiology 305: H634–H643. doi:10.1152/ajpheart.00799.2012.

    Article  CAS  PubMed  Google Scholar 

  • Rindler, P.M., S.M. Plafker, L.I. Szweda, and M. Kinter. 2013b. High dietary fat selectively increases catalase expression within cardiac mitochondria. The Journal of Biological Chemistry 288: 1979–1990. doi:10.1074/jbc.M112.412890.

    Article  CAS  PubMed  Google Scholar 

  • Rother, K.I., Y. Imai, M. Caruso, F. Beguinot, P. Formisano, and D. Accili. 1998. Evidence that IRS-2 phosphorylation is required for insulin action in hepatocytes. The Journal of Biological Chemistry 273: 17491–17497.

    Article  CAS  PubMed  Google Scholar 

  • Ruderman, N.B., A.K. Saha, D. Vavvas, and L.A. Witters. 1999. Malonyl-CoA, fuel sensing, and insulin resistance. The American Journal of Physiology 276: E1–E18.

    CAS  PubMed  Google Scholar 

  • Ryden, M., A. Dicker, V. van Harmelen, H. Hauner, M. Brunnberg, L. Perbeck, F. Lonnqvist, and P. Arner. 2002. Mapping of early signaling events in tumor necrosis factor-alpha -mediated lipolysis in human fat cells. The Journal of Biological Chemistry 277: 1085–1091. doi:10.1074/jbc.M109498200.

    Article  CAS  PubMed  Google Scholar 

  • Sabio, G., and R.J. Davis. 2010. cJun NH2-terminal kinase 1 (JNK1): Roles in metabolic regulation of insulin resistance. Trends in Biochemical Sciences 35: 490–496. doi:10.1016/j.tibs.2010.04.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saha, P.K., H. Kojima, J. Martinez-Botas, A.L. Sunehag, and L. Chan. 2004. Metabolic adaptations in the absence of perilipin: Increased beta-oxidation and decreased hepatic glucose production associated with peripheral insulin resistance but normal glucose tolerance in perilipin-null mice. The Journal of Biological Chemistry 279: 35150–35158. doi:10.1074/jbc.M405499200.

    Article  CAS  PubMed  Google Scholar 

  • Schafer, F.Q., and G.R. Buettner. 2001. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radical Biology & Medicine 30: 1191–1212.

    Article  CAS  Google Scholar 

  • Schaffer, J.E. 2003. Lipotoxicity: When tissues overeat. Current Opinion in Lipidology 14: 281–287. doi:10.1097/01.mol.0000073508.41685.7f.

    Article  CAS  PubMed  Google Scholar 

  • Schenk, S., and J.F. Horowitz. 2006. Coimmunoprecipitation of FAT/CD36 and CPT I in skeletal muscle increases proportionally with fat oxidation after endurance exercise training. American Journal of Physiology. Endocrinology and Metabolism 291: E254–E260. doi:10.1152/ajpendo.00051.2006.

    Article  CAS  PubMed  Google Scholar 

  • Schmitz-Peiffer, C. 2000. Signalling aspects of insulin resistance in skeletal muscle: Mechanisms induced by lipid oversupply. Cellular Signalling 12: 583–594.

    Article  CAS  PubMed  Google Scholar 

  • Schönfeld, P., and L. Wojtczak. 2008. Fatty acids as modulators of the cellular production of reactive oxygen species. Free Radical Biology & Medicine 45: 231–241. doi:10.1016/j.freeradbiomed.2008.04.029.

    Article  CAS  Google Scholar 

  • Schrauwen, P., and M.K.C. Hesselink. 2004. The role of uncoupling protein 3 in fatty acid metabolism: Protection against lipotoxicity? The Proceedings of the Nutrition Society 63: 287–292. doi:10.1079/PNS2003336.

    Article  CAS  PubMed  Google Scholar 

  • Seifert, E.L., C. Estey, J.Y. Xuan, and M.-E. Harper. 2010. Electron transport chain-dependent and -independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation. The Journal of Biological Chemistry 285: 5748–5758. doi:10.1074/jbc.M109.026203.

    Article  CAS  PubMed  Google Scholar 

  • Seiler, S.E., O.J. Martin, R.C. Noland, D.H. Slentz, K.L. DeBalsi, O.R. Ilkayeva, J. An, C.B. Newgard, T.R. Koves, and D.M. Muoio. 2014. Obesity and lipid stress inhibit carnitine acetyltransferase activity. Journal of Lipid Research 55: 635–644. doi:10.1194/jlr.M043448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Senapedis, W.T., C.J. Kennedy, P.M. Boyle, and P.A. Silver. 2011. Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain. Molecular Biology of the Cell 22: 1791–1805. doi:10.1091/mbc.E10-10-0854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shao, W., and P.J. Espenshade. 2014. Sterol regulatory element-binding protein (SREBP) cleavage regulates Golgi-to-endoplasmic reticulum recycling of SREBP cleavage-activating protein (SCAP). The Journal of Biological Chemistry 289: 7547–7557. doi:10.1074/jbc.M113.545699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi, H., M.V. Kokoeva, K. Inouye, I. Tzameli, H. Yin, and J.S. Flier. 2006. TLR4 links innate immunity and fatty acid-induced insulin resistance. The Journal of Clinical Investigation 116: 3015–3025. doi:10.1172/JCI28898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimomura, I., M. Matsuda, R.E. Hammer, Y. Bashmakov, M.S. Brown, and J.L. Goldstein. 2000. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Molecular Cell 6: 77–86.

    Article  CAS  PubMed  Google Scholar 

  • Shoelson, S.E., L. Herrero, and A. Naaz. 2007. Obesity, inflammation, and insulin resistance. Gastroenterology 132: 2169–2180. doi:10.1053/j.gastro.2007.03.059.

    Article  CAS  PubMed  Google Scholar 

  • Shulman, G.I. 2000. Cellular mechanisms of insulin resistance. The Journal of Clinical Investigation 106: 171–176. doi:10.1172/JCI10583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith, S.R., and E. Ravussin. 2002. Emerging paradigms for understanding fatness and diabetes risk. Current Diabetes Reports 2: 223–230.

    Article  PubMed  Google Scholar 

  • Son, N.-H., S. Yu, J. Tuinei, K. Arai, H. Hamai, S. Homma, G.I. Shulman, E.D. Abel, and I.J. Goldberg. 2010. PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation. The Journal of Clinical Investigation 120: 3443–3454. doi:10.1172/JCI40905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sparagna, G.C., D.L. Hickson-Bick, L.M. Buja, and J.B. McMillin. 2001. Fatty acid-induced apoptosis in neonatal cardiomyocytes: Redox signaling. Antioxidants & Redox Signaling 3: 71–79. doi:10.1089/152308601750100524.

    Article  CAS  Google Scholar 

  • Stratford, S., K.L. Hoehn, F. Liu, and S.A. Summers. 2004. Regulation of insulin action by ceramide: Dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. The Journal of Biological Chemistry 279: 36608–36615. doi:10.1074/jbc.M406499200.

    Article  CAS  PubMed  Google Scholar 

  • Summers, S.A. 2006. Ceramides in insulin resistance and lipotoxicity. Progress in Lipid Research 45: 42–72. doi:10.1016/j.plipres.2005.11.002.

    Article  CAS  PubMed  Google Scholar 

  • Summers, S.A., and D.H. Nelson. 2005. A role for sphingolipids in producing the common features of type 2 diabetes, metabolic syndrome X, and Cushing’s syndrome. Diabetes 54: 591–602.

    Article  CAS  PubMed  Google Scholar 

  • Summers, S.A., L.A. Garza, H. Zhou, and M.J. Birnbaum. 1998. Regulation of insulin-stimulated glucose transporter GLUT4 translocation and Akt kinase activity by ceramide. Molecular and Cellular Biology 18: 5457–5464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Symons, J.D., and E.D. Abel. 2013. Lipotoxicity contributes to endothelial dysfunction: A focus on the contribution from ceramide. Reviews in Endocrine & Metabolic Disorders 14: 59–68. doi:10.1007/s11154-012-9235-3.

    Article  CAS  Google Scholar 

  • Szendroedi, J., T. Yoshimura, E. Phielix, C. Koliaki, M. Marcucci, D. Zhang, T. Jelenik, J. Müller, C. Herder, P. Nowotny, G.I. Shulman, and M. Roden. 2014. Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans. Proceedings of the National Academy of Sciences of the United States of America 111: 9597–9602. doi:10.1073/pnas.1409229111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takano, A., I. Usui, T. Haruta, J. Kawahara, T. Uno, M. Iwata, and M. Kobayashi. 2001. Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin. Molecular and Cellular Biology 21: 5050–5062. doi:10.1128/MCB.21.15.5050-5062.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tansey, J.T., C. Sztalryd, E.M. Hlavin, A.R. Kimmel, and C. Londos. 2004. The central role of perilipin a in lipid metabolism and adipocyte lipolysis. IUBMB Life 56: 379–385. doi:10.1080/15216540400009968.

    Article  CAS  PubMed  Google Scholar 

  • Timmers, S., P. Schrauwen, and J. de Vogel. 2008. Muscular diacylglycerol metabolism and insulin resistance. Physiology & Behavior 94: 242–251. doi:10.1016/j.physbeh.2007.12.002.

    Article  CAS  Google Scholar 

  • Ueki, K., T. Kondo, and C.R. Kahn. 2004. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Molecular and Cellular Biology 24: 5434–5446. doi:10.1128/MCB.24.12.5434-5446.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Unger, R.H. 2002. Lipotoxic diseases. Annual Review of Medicine 53: 319–336. doi:10.1146/annurev.med.53.082901.104057.

    Article  CAS  PubMed  Google Scholar 

  • ———. 2003a. Minireview: Weapons of lean body mass destruction: The role of ectopic lipids in the metabolic syndrome. Endocrinology 144: 5159–5165. doi:10.1210/en.2003-0870.

    Article  CAS  PubMed  Google Scholar 

  • ———. 2003b. Lipid overload and overflow: Metabolic trauma and the metabolic syndrome. Trends in Endocrinology and Metabolism 14: 398–403.

    Article  CAS  PubMed  Google Scholar 

  • Unger, R.H., and P.E. Scherer. 2010. Gluttony, sloth and the metabolic syndrome: A roadmap to lipotoxicity. Trends in Endocrinology and Metabolism 21: 345–352. doi:10.1016/j.tem.2010.01.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valdecantos, M.P., P.L. Prieto-Hontoria, V. Pardo, T. Módol, B. Santamaría, M. Weber, L. Herrero, D. Serra, J. Muntané, A. Cuadrado, M.J. Moreno-Aliaga, J. Alfredo Martínez, and Á.M. Valverde. 2015. Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes. Free Radical Biology & Medicine 84: 263–278. doi:10.1016/j.freeradbiomed.2015.03.019.

    Article  CAS  Google Scholar 

  • Wang, H., and C. Sztalryd. 2011. Oxidative tissue: Perilipin 5 links storage with the furnace. Trends Endocrinol Metab 22: 197–203. doi:10.1016/j.tem.2011.03.008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang, H., U. Sreenivasan, U. Sreenevasan, H. Hu, A. Saladino, B.M. Polster, L.M. Lund, D. Gong, W.C. Stanley, and C. Sztalryd. 2011. Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria. Journal of Lipid Research 52: 2159–2168. doi:10.1194/jlr.M017939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, X.L., L. Zhang, K. Youker, M.-X. Zhang, J. Wang, S.A. LeMaire, J.S. Coselli, and Y.H. Shen. 2006. Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Diabetes 55: 2301–2310. doi:10.2337/db05-1574.

    Article  CAS  PubMed  Google Scholar 

  • Watkins, P.A. 2008. Very-long-chain acyl-CoA synthetases. The Journal of Biological Chemistry 283: 1773–1777. doi:10.1074/jbc.R700037200.

    Article  CAS  PubMed  Google Scholar 

  • Wellen, K.E., and G.S. Hotamisligil. 2003. Obesity-induced inflammatory changes in adipose tissue. The Journal of Clinical Investigation 112: 1785–1788. doi:10.1172/JCI20514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • WHO_TRS_916.pdf. (n.d.)

    Google Scholar 

  • Winder, W.W., and D.G. Hardie. 1996. Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. The American Journal of Physiology 270: E299–E304.

    CAS  PubMed  Google Scholar 

  • Xu, C., J. He, H. Jiang, L. Zu, W. Zhai, S. Pu, and G. Xu. 2009. Direct effect of glucocorticoids on lipolysis in adipocytes. Molecular Endocrinology 23: 1161–1170. doi:10.1210/me.2008-0464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ye, J. 2013. Mechanisms of insulin resistance in obesity. Frontiers in Medicine 7: 14–24. doi:10.1007/s11684-013-0262-6.

    Article  Google Scholar 

  • Ying, W. 2008. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: Regulation and biological consequences. Antioxidants & Redox Signaling 10: 179–206. doi:10.1089/ars.2007.1672.

    Article  CAS  Google Scholar 

  • Young, M.E., G.W. Goodwin, J. Ying, P. Guthrie, C.R. Wilson, F.A. Laws, and H. Taegtmeyer. 2001. Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids. American Journal of Physiology. Endocrinology and Metabolism 280: E471–E479.

    CAS  PubMed  Google Scholar 

  • Yu, C., Y. Chen, G.W. Cline, D. Zhang, H. Zong, Y. Wang, R. Bergeron, J.K. Kim, S.W. Cushman, G.J. Cooney, B. Atcheson, M.F. White, E.W. Kraegen, and G.I. Shulman. 2002. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. The Journal of Biological Chemistry 277: 50230–50236. doi:10.1074/jbc.M200958200.

    Article  CAS  PubMed  Google Scholar 

  • Yuan, H., X. Zhang, X. Huang, Y. Lu, W. Tang, Y. Man, S. Wang, J. Xi, and J. Li. 2010. NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of β-cells via JNK, p38 MAPK and p53 pathways. PLoS One 5: e15726. doi:10.1371/journal.pone.0015726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuzefovych, L., G. Wilson, and L. Rachek. 2010. Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: Role of oxidative stress. American Journal of Physiology. Endocrinology and Metabolism 299: E1096–E1105. doi:10.1152/ajpendo.00238.2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zámbó, V., L. Simon-Szabó, P. Szelényi, E. Kereszturi, G. Bánhegyi, and M. Csala. 2013. Lipotoxicity in the liver. World Journal of Hepatology 5: 550–557. doi:10.4254/wjh.v5.i10.550.

    PubMed  PubMed Central  Google Scholar 

  • Zehmer, J.K., Y. Huang, G. Peng, J. Pu, R.G.W. Anderson, and P. Liu. 2009. A role for lipid droplets in inter-membrane lipid traffic. Proteomics 9: 914–921. doi:10.1002/pmic.200800584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhande, R., J.J. Mitchell, J. Wu, and X.J. Sun. 2002. Molecular mechanism of insulin-induced degradation of insulin receptor substrate 1. Molecular and Cellular Biology 22: 1016–1026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, D.D. 2006. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metabolism Reviews 38: 769–789. doi:10.1080/03602530600971974.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, H.H., M. Halbleib, F. Ahmad, V.C. Manganiello, and A.S. Greenberg. 2002. Tumor necrosis factor-alpha stimulates lipolysis in differentiated human adipocytes through activation of extracellular signal-related kinase and elevation of intracellular cAMP. Diabetes 51: 2929–2935.

    Article  CAS  PubMed  Google Scholar 

  • Zouhal, H., S. Lemoine-Morel, M.-E. Mathieu, G.A. Casazza, and G. Jabbour. 2013. Catecholamines and obesity: Effects of exercise and training. Sports Medicine 43: 591–600. doi:10.1007/s40279-013-0039-8.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey

    Ayse Basak Engin Ph.D., Ph.D.

Authors
  1. Ayse Basak Engin Ph.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ayse Basak Engin Ph.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey

    Ayse Basak Engin

  2. Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey

    Atilla Engin

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Engin, A.B. (2017). What Is Lipotoxicity?. In: Engin, A., Engin, A. (eds) Obesity and Lipotoxicity. Advances in Experimental Medicine and Biology, vol 960. Springer, Cham. https://doi.org/10.1007/978-3-319-48382-5_8

Download citation

Publish with us

Policies and ethics

Search

Navigation