Abstract
The potential lipotoxic effect of intramyocellular triglyceride (IMTG) accumulation has been suggested to be a major component in the development of insulin resistance. Increased levels of IMTGs correlate with insulin resistance in both obese and diabetic patients, but this relationship does not exist in endurance trained (ETr) subjects. This may be, in part, related to differences in the gene expression and activities of key enzymes involved in fatty acid transport and oxidation as well as in the perodixation status of the IMTGs in obese/diabetic patients as compared with ETr subjects. Disruptions in fat and lipid homeostasis in skeletal muscle have been shown to activate protein kinase C (PKC), which acts on several downstream signalling pathways, including the insulin and the IκB kinase (IKK)/NFκB signalling pathways. Additionally, an increased peroxidation of IMTGs may reduce insulin sensitivity by increasing TNFα, which is known to increase the expression of suppressor of cytokine signalling proteins (SOCS). A common characteristic observed when activating both PKC and TNFα/SOCS3 is the inhibition of tyrosine phosphorylation of IRS-1 and subsequently an inhibition of its activation of downstream signalling molecules. These may be important players in the development of insulin resistance and understanding their activation and expression in both obese and ETr humans should assist in understanding how and why IMTGs become lipotoxic.
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References
Goodpaster BH, Kelley DE . Skeletal muscle triglyceride: marker or mediator of obesity-induced insulin resistance in type 2 diabetes mellitus? Curr Diab Rep 2002; 2: 216–222.
Schaffer JE . Lipotoxicity: when tissues overeat. Curr Opin Lipidol 2003; 14: 281–287.
Goodpaster BH, He J, Watkins S, Kelley DE . Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 2001; 86: 5755–5761.
Boesch C, Slotboom J, Hoppeler H, Kreis R . In vivo determination of intra-myocellular lipids in human muscle by means of localized 1H-MR-spectroscopy. Magn Reson Med 1997; 37: 484–493.
Simoneau JA, Veerkamp JH, Turcotte LP, Kelley DE . Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB J 1999; 13: 2051–2060.
Kelley DE, Goodpaster B, Wing RR, Simoneau JA . Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am J Physiol 1999; 277: E1130–E1141.
Morgan TE, Short FA, Cobb LA . Effect of long-term exercise on skeletal muscle lipid composition. Am J Physiol 1969; 216: 82–86.
Hoppeler H, Howald H, Conley K, Lindstedt SL, Claassen H, Vock P, Weibel ER . Endurance training in humans: aerobic capacity and structure of skeletal muscle. J Appl Physiol 1985; 59: 320–327.
Russell AP, Gastaldi G, Bobbioni-Harsch E, Arboit P, Gobelet C, Dériaz O, Golay A, Witztum JL, Giacobino JP . Lipid peroxidation in skeletal muscle of obese as compared to endurance trained humans: a case of good vs bad lipids? FEBS Lett 2003; 551: 104–106.
Kiens B . Training and fatty acid metabolism. Adv Exp Med Biol 1998; 441: 229–238.
Jong-Yeon K, Hickner RC, Dohm GL, Houmard JA . Long- and medium-chain fatty acid oxidation is increased in exercise-trained human skeletal muscle. Metabolism 2002; 51: 460–464.
Starritt EC, Howlett RA, Heigenhauser GJ, Spriet LL . Sensitivity of CPT I to malonyl-CoA in trained and untrained human skeletal muscle. Am J Physiol Endocrinol Metab 2000; 278: E462–E468.
Carter SL, Rennie CD, Hamilton SJ, Tarnopolsky . Changes in skeletal muscle in males and females following endurance training. Can J Physiol Pharmacol 2001; 79: 386–392.
Russell A, Wadley G, Snow R, Giacobino JP, Muzzin P, Garnham A, Cameron-Smith D . Slow component of VO2 kinetics: the effect of training status, fibre type, UCP3 mRNA and citrate synthase activity. Int J Obes Relat Metab Disord 2002; 26: 157–164.
Russell AP, Feilchenfeldt J, Schreiber S, Praz M, Crettenand A, Gobelet C, Meier CA, Bell DR, Kralli A, Giacobino JP, Deriaz O . Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle. Diabetes 2003; 52: 2874–2881.
Siu PM, Donley DA, Bryner RW, Alway SE . Citrate synthase expression and enzyme activity after endurance training in cardiac and skeletal muscles. J Appl Physiol 2003; 94: 555–560.
Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, Coenen-Schimke JM, Nair KS . Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes 2003; 52: 1888–1896.
Zierler KL . Fatty acids as substrates for heart and skeletal muscle. Circ Res 1976; 38: 459–463.
Watt MJ, Heigenhauser GJ, Spriet LL . Intramuscular triacylglycerol utilization in human skeletal muscle during exercise: is there a controversy? J Appl Physiol 2002; 93: 1185–1195.
Essen B, Jansson E, Henriksson J, Taylor AW, Saltin B . Metabolic characteristics of fibre types in human skeletal muscle. Acta Physiol Scand 1975; 95: 153–165.
Kjaer M, Howlett K, Langfort J, Zimmerman-Belsing T, Lorentsen J, Bulow J, Ihlemann J, Feldt-Rasmussen U, Galbo H . Adrenaline and glycogenolysis in skeletal muscle during exercise: a study in adrenalectomised humans. J Physiol 2000; 528: 371–378.
Peters SJ, Dyck DJ, Bonen A, Spriet LL . Effects of epinephrine on lipid metabolism in resting skeletal muscle. Am J Physiol 1998; 275: E300–E309.
Langfort J, Ploug T, Ihlemann J, Holm C, Galbo H . Stimulation of hormone-sensitive lipase activity by contractions in rat skeletal muscle. Biochem J 2000; 351: 207–214.
Ray H, Beylot M, Arner P, Larrouy D, Langin D, Holm C, Large V . The presence of a catalytically inactive form of hormone-sensitive lipase is associated with decreased lipolysis in abdominal subcutaneous adipose tissue of obese subjects. Diabetes 2003; 52: 1417–1422.
Winzell MS, Holm C, Ahren B . Downregulation of islet hormone-sensitive lipase during long-term high-fat feeding. Biochem Biophys Res Commun 2003; 304: 273–278.
Boden G . Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997; 46: 3–10.
Boden G, Jadali F, White J, Liang Y, Mozzoli M, Chen X, Coleman E, Smith C . Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest 1991; 88: 960–966.
Boden G, Lebed B, Schatz M, Homko C, Lemieux S . Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 2001; 50: 1612–1617.
Brechtel K, Dahl DB, Machann J, Bachmann OP, Wenzel I, Maier T, Claussen CD, Haring HU, Jacob S, Schick F . Fast elevation of the intramyocellular lipid content in the presence of circulating free fatty acids and hyperinsulinemia: a dynamic 1H-MRS study. Magn Reson Med 2001; 45: 179–183.
Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, Arcelloni C, Vanzulli A, Testolin G, Pozza G, Del Maschio A, Luzi L . Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes 1999; 48: 1600–1606.
Virkamaki A, Korsheninnikova E, Seppala-Lindroos A, Vehkavaara S, Goto T, Halavaara J, Hakkinen AM, Yki-Jarvinen H . Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle. Diabetes 2001; 50: 2337–2343.
Dela F, Larsen JJ, Mikines KJ, Ploug T, Petersen LN, Galbo H . Insulin-stimulated muscle glucose clearance in patients with NIDDM. Effects of one-legged physical training. Diabetes 1995; 44: 1010–1020.
Mayer-Davis EJ, D'Agostino Jr R, Karter AJ, Haffner SM, Rewers MJ, Saad M, Bergman RN . Intensity and amount of physical activity in relation to insulin sensitivity: the Insulin Resistance Atherosclerosis Study. JAMA 1998; 279: 669–674.
Malenfant P, Joanisse DR, Theriault R, Goodpaster BH, Kelley DE, Simoneau JA . Fat content in individual muscle fibers of lean and obese subjects. Int J Obes Relat Metab Disord 2001; 25: 1316–1321.
Krotkiewski M . Role of muscle morphology in the development of insulin resistance and metabolic syndrome. Presse Med 1994; 23: 1393–1399.
Thompson AL, Cooney GJ . Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance. Diabetes 2000; 49: 1761–1765.
Schmitz-Peiffer C, Browne CL, Oakes ND, Watkinson A, Chisholm DJ, Kraegen EW, Biden TJ . Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat. Diabetes 1997; 46: 169–178.
Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI . Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 2002; 277: 50230–50236.
Bronfman M, Morales MN, Orellana A . Diacylglycerol activation of protein kinase C is modulated by long-chain acyl-CoA. Biochem Biophys Res Commun 1988; 152: 987–992.
Nishizuka Y . Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 1995; 9: 484–496.
Itani SI, Zhou Q, Pories WJ, MacDonald KG, Dohm GL . Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. Diabetes 2000; 49: 1353–1358.
Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI . Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999; 48: 1270–1274.
Itani SI, Ruderman NB, Schmieder F, Boden G . Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002; 51: 2005–2011.
Standaert ML, Ortmeyer HK, Sajan MP, Kanoh Y, Bandyopadhyay G, Hansen BC, Farese RV . Skeletal muscle insulin resistance in obesity-associated type 2 diabetes in monkeys is linked to a defect in insulin activation of protein kinase C-zeta/lambda/iota. Diabetes 2002; 51: 2936–2943.
Ghosh S, Baltimore D . Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature 1990; 344: 678–682.
Barnes PJ, Karin M . Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336: 1066–1071.
Schmitz-Peiffer C, Craig DL, Biden TJ . Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. J Biol Chem 1999; 274: 24202–24210.
MacDonald GA, Bridle KR, Ward PJ, Walker NI, Houglum K, George DK, Smith JL, Powell LW, Crawford DH, Ramm GA . Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3. J Gastroenterol Hepatol 2001; 16: 599–606.
Glass CK, Witztum JL . Atherosclerosis, the road ahead. Cell 2001; 104: 503–516.
Kuno T, Hozumi M, Morinobu T, Murata T, Mingci Z, Tamai H . Antioxidant vitamin levels in plasma and low density lipoprotein of obese girls. Free Radic Res 1998; 28: 81–86.
Dandona P, Mohanty P, Ghanim H, Aljada A, Browne R, Hamouda W, Prabhala A, Afzal A, Garg R . The suppressive effect of dietary restriction and weight loss in the obese on the generation of reactive oxygen species by leukocytes, lipid peroxidation, and protein carbonylation. J Clin Endocrinol Metab 2001; 86: 355–362.
Palinski W, Yla-Herttuala S, Rosenfeld ME, Butler SW, Socher SA, Parthasarathy S, Curtiss LK, Witztum JL . Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein. Arteriosclerosis 1990; 10: 325–335.
Donica H . Evaluation of lipids peroxidation products vs proinflammatory cytokines in hemodialized patients. Renal Failure 2001; 23: 231–238.
Zhou Z, Wang L, Song Z, Lambert JC, McClain CJ, Kang YJ . A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-alpha production. Am J Pathol 2003; 163: 1137–1146.
Mingrone G, Rosa G, Di Rocco P, Manco M, Capristo E, Castagneto M, Vettor R, Gasbarrini G, Greco AV . Skeletal muscle triglycerides lowering is associated with net improvement of insulin sensitivity, TNF-alpha reduction and GLUT4 expression enhancement. Int J Obes Relat Metab Disord 2002; 26: 1165–1172.
Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, Hotamisligil GS, Van Obberghen E . SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 2001; 276: 47944–47949.
Criswell D, Powers S, Dodd S, Lawler J, Edwards W, Renshler K, Grinton S . High intensity training-induced changes in skeletal muscle antioxidant enzyme activity. Med Sci Sports Exerc 1993; 25: 1135–1140.
Sen CK . Oxidants and antioxidants in exercise. J Appl Physiol 1995; 79: 675–686.
Venditti P, Di Meo S . Antioxidants, tissue damage, and endurance in trained and untrained young male rats. Arch Biochem Biophys 1996; 331: 63–68.
Greiwe JS, Cheng B, Rubin DC, Yarasheski KE, Semenkovich CF . Resistance exercise decreases skeletal muscle tumor necrosis factor alpha in frail elderly humans. FASEB J 2001; 15: 475–482.
Russell AP, Somm E, Praz M, Crettenand A, Hartley O, Melotti A, Giacobino JP, Muzzin P, Gobelet C, Deriaz O . UCP3 protein regulation in human skeletal muscle fibre types I, IIa and IIx is dependent on exercise intensity. J Physiol 2003; 550: 855–861.
Fitts RH, Widrick JJ . Muscle mechanics: adaptations with exercise-training. Exerc Sport Sci Rev 1996; 24: 427–473.
Carter SL, Rennie C, Tarnopolsky MA . Substrate utilization during endurance exercise in men and women after endurance training. Am J Physiol Endocrinol Metab 2001; 280: E898–E907.
Schrauwen P, van Aggel-Leijssen DP, Hul G, Wagenmakers AJ, Vidal H, Saris WH, van Baak MA . The effect of a 3-month low-intensity endurance training program on fat oxidation and acetyl-CoA carboxylase-2 expression. Diabetes 2002; 51: 2220–2226.
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Russell, A. Lipotoxicity: the obese and endurance-trained paradox. Int J Obes 28 (Suppl 4), S66–S71 (2004). https://doi.org/10.1038/sj.ijo.0802859
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