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Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity

International Journal of Obesity volume 28, pages S29–S37 (2004)Cite this article

Abstract

Life is a combustion, but how the major fuel substrates that sustain human life compete and interact with each other for combustion has been at the epicenter of research into the pathogenesis of insulin resistance ever since Randle proposed a ‘glucose–fatty acid cycle’ in 1963. Since then, several features of a mutual interaction that is characterized by both reciprocality and dependency between glucose and lipid metabolism have been unravelled, namely:

  1. i)

    the inhibitory effects of elevated concentrations of fatty acids on glucose oxidation (via inactivation of mitochondrial pyruvate dehydrogenase or via desensitization of insulin-mediated glucose transport),

  2. ii)

    the inhibitory effects of elevated concentrations of glucose on fatty acid oxidation (via malonyl-CoA regulation of fatty acid entry into the mitochondria), and more recently

  3. iii)

    the stimulatory effects of elevated concentrations of glucose on de novo lipogenesis, that is, synthesis of lipids from glucose (via SREBP1c regulation of glycolytic and lipogenic enzymes).

This paper first revisits the physiological significance of these mutual interactions between glucose and lipids in skeletal muscle pertaining to both blood glucose and intramyocellular lipid homeostasis. It then concentrates upon emerging evidence, from calorimetric studies investigating the direct effect of leptin on thermogenesis in intact skeletal muscle, of yet another feature of the mutual interaction between glucose and lipid oxidation: that of substrate cycling between de novo lipogenesis and lipid oxidation. It is proposed that this energy-dissipating substrate cycling that links glucose and lipid metabolism to thermogenesis could function as a ‘fine-tuning’ mechanism that regulates intramyocellular lipid homeostasis, and hence contributes to the protection of skeletal muscle against lipotoxicity.

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References

  1. Neel JV, Weder AB, Julius S . Type II diabetes, essential hypertension, and obesity as ‘syndromes of impaired genetic homeostasis’: the ‘thrifty genotype’ hypothesis enters the 21st century. Perspect Biol Med 1998; 42: 44–75.

    Article  CAS  Google Scholar 

  2. Landsberg L . Diet, obesity and hypertension: a hypothesis involving insulin, the sympathetic nervous system and adaptive thermogenesis. Q J Med 1986; 61: 1081–1090.

    CAS  PubMed  Google Scholar 

  3. Landsberg L . Insulin-mediated sympathetic stimulation: role in the pathogenesis of obesity-related hypertension (or, how insulin affects blood pressure, and why). J Hypertens 2001; 19: 523–528.

    Article  CAS  Google Scholar 

  4. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP . The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 1981; 30: 1000–1007.

    Article  CAS  Google Scholar 

  5. DeFronzo RA . Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988; 37: 667–687.

    Article  CAS  Google Scholar 

  6. Petersen KF, Schulman GI . Pathogenesis of skeletal muscle insulin resistance in type 2 diabetes mellitus. Am J Cardiol 2002; 90 (Suppl): 11G–18G.

    Article  CAS  Google Scholar 

  7. Rothman DL, Magnusson I, Cline G, Gerard D, Kahn CR, Shulman RG, Shulman GI . Decreased muscle glucose transport/phosphorylation is an early defect in the pathogenesis of non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 1995; 92: 983–987.

    Article  CAS  Google Scholar 

  8. Roden M, Shulman GI . Applications of NMR spectroscopy to study muscle glycogen metabolism in man. Annu Rev Med 1999; 50: 277–290.

    Article  CAS  Google Scholar 

  9. Reaven GM . Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607.

    Article  CAS  Google Scholar 

  10. Felig P, Marliss E, Cahill Jr GF . GF Plasma amino acid levels and insulin secretion in obesity. N Engl J Med 1969; 281: 811–816.

    Article  CAS  Google Scholar 

  11. Felber JP, Golay A . Pathways from obesity to diabetes. Int J Obes Relat Metab Disord 2002; 26 (Suppl 2): S39–S45.

    Article  CAS  Google Scholar 

  12. Krebs M, Roden M . Nutrient-induced insulin resistance in human skeletal muscle. Curr Med Chem 2004; 11: 907–908.

    Article  Google Scholar 

  13. Richter EA, Hansen BF, Hansen SA . Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake. Biochem J 1988; 252: 733–737.

    Article  CAS  Google Scholar 

  14. Laybutt DR, Schmitz-Peiffer C, Saha AK, Ruderman NB, Biden TJ, Kraegen EW . Muscle lipid accumulation and protein kinase C activation in the insulin-resistant chronically glucose-infused rat. Am J Physiol 1999; 277: E1070–E1076.

    CAS  PubMed  Google Scholar 

  15. Hegarty BD, Furler SM, Ye J, Cooney GJ, Kraegen EW . The role of intramuscular lipid in insulin resistance. Acta Physiol Scand 2003; 178: 373–383.

    Article  CAS  Google Scholar 

  16. Benedict FG, Joslin EP . Metabolism in Diabetes Mellitus. Carnegie Institute of Washington: Washington DC, USA, Publication 136; 1910. pp 3–234.

    Google Scholar 

  17. Cahill Jr GF, Owen OE . Some observations on carbohydrate metabolism in man. In: Dickens F, Randle PJ, Whelan WJ (eds). Carbohydrate metabolism and its disorders. Academic Press: London; 1968. pp 497–522.

    Google Scholar 

  18. Krebs HA . Metabolism of amino acids. III. Deamination of amino acids. Biochem J 1935; 29: 1620–1644.

    Article  CAS  Google Scholar 

  19. Waters ET, Fletcher JP, Mirsky IA . Relation between carbohydrate and 3-hydroxybutyrate utilization by heart lung preparations. Am J Physiol 1938; 122: 542–546.

    Article  CAS  Google Scholar 

  20. Newsholme EA, Manchester KL, Randle PJ . Inhibition of the phosphofructokinase reaction in perfused rat heart by respiration of ketone bodies, fatty acids and pyruvate. Nature 1962; 193: 270–271.

    Article  CAS  Google Scholar 

  21. Garland PB, Newsholme EA, Randle PJ . Effect of fatty acids, ketone bodies, diabetes and starvation on pyruvate metabolism in rat heart and diaphragm muscle. Nature 1962; 195: 381–383.

    Article  CAS  Google Scholar 

  22. Randle PJ, Garland PB, Hales CN, Newsholme EA . The glucose–fatty acid cycle: its role in insulin sensitivity and metabolic disturbances of diabetes mellitus. Lancet 1963; i: 785–789.

    Article  Google Scholar 

  23. Randle PJ, Garland PB, Hales CN, Newsholme EA, Denton RM, Pogson CI . Interactions of metabolism and physiological role of insulin. Recent Prog Horm Res 1966; 22: 1–48.

    CAS  PubMed  Google Scholar 

  24. Randle PJ . Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 1998; 14: 263–283.

    Article  CAS  Google Scholar 

  25. Frayn KN . The glucose–fatty acid cycle: a physiological perspective. Biochem Soc Trans 2003; 31: 1115–1119.

    Article  CAS  Google Scholar 

  26. Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA . Effect of fatty acids on glucose production and utilization in man. J Clin Invest 1983; 72: 1737–1747.

    Article  CAS  Google Scholar 

  27. Kelley DE, Mokan M, Simoneau JA, Mandarino LJ . Interaction between glucose and free fatty acid metabolism in human skeletal muscle. J Clin Invest 1993; 92: 91–98.

    Article  CAS  Google Scholar 

  28. Boden G, Chen X, Ruiz J, White JV, Rossetti L . Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 1994; 93: 2438–2446.

    Article  CAS  Google Scholar 

  29. Boden G . Interaction between free fatty acids and glucose metabolism. Curr Opin Clin Nutr Metab Care 2002; 5: 545–549.

    Article  CAS  Google Scholar 

  30. Bjornholm M, Kawano Y, Lehtihet M, Zierath JR . Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 1997; 46: 524–527.

    Article  CAS  Google Scholar 

  31. Kahn BB . Glucose transport: pivotal step in insulin action. Diabetes 1996; 45: 1644–1654.

    Article  CAS  Google Scholar 

  32. McGarry JD, Mannaerts GP, Foster DW . A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J Clin Invest 1977; 60: 265–270.

    Article  CAS  Google Scholar 

  33. McGarry JD . Glucose-fatty acid interactions in health and disease. Am J Clin Nutr 1998; 67 (Suppl): 500S–504S.

    Article  CAS  Google Scholar 

  34. Nugteren DH . The enzymic chain elongation of fatty acids by rat-liver microsomes. Biochim Biophys Acta 1965; 106: 280–290.

    Article  CAS  Google Scholar 

  35. Bianchi A, Evans JL, Iverson AJ, Nordlund AC, Watts TD, Witters LA . Identification of an isozymic form of acetyl-CoA carboxylase. J Biol Chem 1990; 265: 1502–1509.

    CAS  PubMed  Google Scholar 

  36. Ha J, Lee JK, Kim KS, Witters LA, Kim KH . Cloning of human acetyl-CoA carboxylase-beta and its unique features. Proc Natl Acad Sci USA 1996; 93: 11466–11470.

    Article  CAS  Google Scholar 

  37. Abu-Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G, Wakil SJ . The subcellular localization of acetyl-CoA carboxylase 2. Proc Natl Acad Sci USA 2000; 97: 1444–1449.

    Article  CAS  Google Scholar 

  38. Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ . Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 2001; 291: 2613–2616.

    Article  CAS  Google Scholar 

  39. Alam N, Saggerson ED . Malonyl-CoA and the regulation of fatty acid oxidation in soleus muscle. Biochem J 1998; 334: 233–241.

    Article  CAS  Google Scholar 

  40. Jayakumar A, Tai MH, Huang WY, al-Feel W, Hsu M, Abu-Elheiga L, Chirala SS, Wakil SJ . Human fatty acid synthase: properties and molecular cloning. Proc Natl Acad Sci USA 1995; 92: 8695–8699.

    Article  CAS  Google Scholar 

  41. Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS . Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J Clin Invest 1997; 99: 838–845.

    Article  CAS  Google Scholar 

  42. Ducluzeau PH, Perretti N, Laville M, Andreelli F, Vega N, Riou JP, Vidal H . Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. Diabetes 2001; 50: 1134–1142.

    Article  CAS  Google Scholar 

  43. Sewter C, Berger D, Considine RV, Medina G, Rochford J, Ciaraldi T, Henry R, Dohm L, Flier JS, O'Rahilly S, Vidal-Puig AJ . Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha. Diabetes 2002; 51: 1035–1041.

    Article  CAS  Google Scholar 

  44. Guillet-Deniau I, Mieulet V, Le Lay S, Achouri Y, Carre D, Girard J, Foufelle F, Ferre P . Sterol regulatory element binding protein-1c expression and action in rat muscles: insulin-like effects on the control of glycolytic and lipogenic enzymes and UCP3 gene expression. Diabetes 2002; 51: 1722–1728.

    Article  CAS  Google Scholar 

  45. Bizeau ME, MacLean PS, Johnson GC, Wei Y . Skeletal muscle sterol regulatory element binding protein-1c decreases with food deprivation and increases with feeding in rats. J Nutr 2003; 133: 1787–1792.

    Article  CAS  Google Scholar 

  46. Commerford SR, Peng L, Dube JJ, O'Doherty RM . In vivo regulation of SREBP-1c in skeletal muscle: effects of nutritional status, glucose, insulin, and leptin. Am J Physiol 2004; 287: R218–R227.

    Article  CAS  Google Scholar 

  47. Guillet-Deniau I, Pichard AL, Koné A, Esnous C, Nieruchalski M, Girard J, Prip-Buus C . Glucose induces de novo lipogenesis in rat muscle satellite cells through a sterol-regulatory-element-binding-protein-1c-dependent pathway. J Cell Sci 2004; 177: 1937–1944.

    Article  Google Scholar 

  48. Aas V, Kase ET, Solberg R, Jensen J, Rustan AC . Chronic hyperglycaemia promotes lipogenesis and triacylglycerol accumulation in human skeletal muscle cells. Diabetologia 2004; 47: 1452–1461.

    Article  CAS  Google Scholar 

  49. Astrup A, Bulow J, Christensen NJ, Madsen J, Quaade F . Facultative thermogenesis induced by carbohydrate: a skeletal muscle component mediated by epinephrine. Am J Physiol 1986; 250: E226–E229.

    CAS  PubMed  Google Scholar 

  50. Schoeller DA, Cella LK, Sinha MK, Caro JF . Entrainment of the diurnal rhythm of plasma leptin to meal timing. J Clin Invest 1997; 100: 1882–1887.

    Article  CAS  Google Scholar 

  51. Evans K, Clark ML, Frayn KN . Carbohydrate and fat have different effects on plasma leptin concentrations and adipose tissue leptin production. Clin Sci 2001; 100: 493–498.

    Article  CAS  Google Scholar 

  52. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F . Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995; 269: 540–543.

    Article  CAS  Google Scholar 

  53. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM . Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269: 543–546.

    Article  CAS  Google Scholar 

  54. Mistry AM, Swick AG, Romsos DR . Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. J Nutr 1997; 127: 2065–2072.

    Article  CAS  Google Scholar 

  55. Rosenbaum M, Murphy EM, Heymsfield SB, Matthews DE, Leibel RL . Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. J Clin Endocrinol Metab 2002; 87: 2391–2394.

    Article  CAS  Google Scholar 

  56. Unger RH, Orci L . Diseases of liporegulation: new perspective on obesity and related disorders. FASEB J 2001; 15: 312–321.

    Article  CAS  Google Scholar 

  57. Ravussin E, Smith SR . Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitus. Ann N Y Acad Sci 2002; 967: 363–378.

    Article  CAS  Google Scholar 

  58. Muoio DM, Lynis Dohm G . Peripheral metabolic actions of leptin. Best Pract Res Clin Endocrinol Metab 2002; 16: 653–666.

    Article  CAS  Google Scholar 

  59. Muoio DM, Dohn GL, Fiedorek FT, Tapscott EB, Coleman RA . Leptin directly alters lipid partitioning in skeletal muscle. Diabetes 1997; 46: 1360–1363.

    Article  CAS  Google Scholar 

  60. Ceddia RB, William Jr WN, Curi R . The response of skeletal muscle to leptin. Front Biosci 2001; 6: D90–D97.

    Article  CAS  Google Scholar 

  61. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB . Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 2002; 415: 339–343.

    Article  CAS  Google Scholar 

  62. Dulloo AG, Stock MJ, Solinas G, Boss O, Montani JP, Seydoux J . Leptin directly stimulates thermogenesis in skeletal muscle. FEBS Lett 2002; 515: 109–113.

    Article  CAS  Google Scholar 

  63. Solinas G, Summermatter S, Mainieri D, Gubler M, Pirola L, Wymann MP, Rusconi S, Montani JP, Seydoux J, Dulloo AG . The direct effect of leptin on skeletal muscle thermogenesis is mediated by substrate cycling between de novo lipogenesis and lipid oxidation. FEBS Lett 2004; 577: 539–544.

    Article  CAS  Google Scholar 

  64. Winder WW, Hardie DG . Inactivation of acetyl-CoA carboxylase and activation of AMP-activated protein kinase in muscle during exercise. Am J Physiol 1996; 270: E299–E304.

    CAS  PubMed  Google Scholar 

  65. Gubler M, Westerberg R, Andjelkovic M, Mizrahi J . Functional characterization of human ACC2 enzyme and elucidation of its role in the regulation of mitochondrial fatty acid oxidation. Keystone Conference on Obesity: New Insights into Pathogenesis and Treatment. Keystone, 2003, Poster Abstract 214.

  66. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T . Adiponectin stimulates glucose utilization and fatty-acid utilization by activating AMP-activated protein kinase. Nat Med 2002; 8: 1288–1295.

    Article  CAS  Google Scholar 

  67. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI, Lodish HF, Ruderman NB . Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetylcoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA 2002; 99: 16309–16313.

    Article  CAS  Google Scholar 

  68. Moule SK, Denton M . The activation of p38 MAPK by the β-adrenergic agonist isoproterenol in rat epididymal fat cells. FEBS Lett 1998; 439: 287–290.

    Article  CAS  Google Scholar 

  69. Yin W, Mu J, Birnbaum MJ . Role of AMP-activated protein kinase in cyclic AMP-dependent lipolysis in 3T3-L1 adipocytes. J Biol Chem 2003; 278: 43074–43080.

    Article  CAS  Google Scholar 

  70. Masaro EJ . Role of lipogenesis in nonshivering thermogenesis. Fed Proc 1963; 22: 868–873.

    Google Scholar 

  71. Ma SWY, Foster DO . Uptake of glucose and release of fatty acids and glycerol by rat brown adipose tissue in vivo. Can J Physiol Pharmacol 1985; 64: 609–614.

    Article  Google Scholar 

  72. Trayhurn P . Fuel selection in brown adipose tissue. Proc Nutr Soc 1995; 54: 39–47.

    Article  CAS  Google Scholar 

  73. Yu XX, Lewin DA, Forrest W, Adams SH . Cold elicits the simultaneous induction of fatty acid synthesis and β-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo. FASEB J 2002; 16: 155–168.

    Article  Google Scholar 

  74. Christoffolete MA, Linardi CC, de Jesus L, Ebina KN, Carvalho SD, Ribeiro MO, Rabelo R, Curcio C, Martins L, Kimura ET, Bianco AC . Mice with targeted disruption of the Dio2 gene have cold-induced overexpression of the uncoupling protein 1 gene but fail to increase brown adipose tissue lipogenesis and adaptive thermogenesis. Diabetes 2004; 53: 577–584.

    Article  CAS  Google Scholar 

  75. Arch JRS . β-3-adrenoceptor agonists: potential, pitfalls and progress. Eur J Pharmacol 2002; 440: 99–107.

    Article  CAS  Google Scholar 

  76. Samec S, Seydoux J, Dulloo AG . Role of UCP homologues in skeletal muscle and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate? FASEB J 1998; 12: 715–724.

    Article  CAS  Google Scholar 

  77. Dulloo AG, Seydoux J, Jacquet J . Adaptive thermogenesis and uncoupling proteins: a reappraisal of their roles in fat metabolism and energy balance. Physiol Behav 2004. (in press).

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Acknowledgements

This work was supported by the Swiss National Science Foundation (grant # 3200B0-102156).

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  1. Department of Medicine, Division of Physiology, University of Fribourg, Switzerland

    A G Dulloo, J P Montani, J Seydoux & G Solinas

  2. Department of Vascular and Metabolic Diseases, Hoffmann-La Roche, Switzerland

    M Gubler

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Correspondence to A G Dulloo.

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Proceedings of the Second Fribourg Obesity Research Conference (FORC-2003)

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Dulloo, A., Gubler, M., Montani, J. et al. Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity. Int J Obes 28 (Suppl 4), S29–S37 (2004). https://doi.org/10.1038/sj.ijo.0802861

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