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Ectopic Fat Accumulation and Glucose Homeostasis: Ectopic Fat Accumulation in Muscle

  • Katsuhito MoriEmail author
  • Tomoaki Morioka
  • Koka Motoyama
  • Masanori Emoto
Chapter

Abstract

Adipocytes can serve as energy storage reservoirs against calorie overload. Beyond its capacity, the spillover of stored energy from adipose tissue results in ectopic fat accumulation in tissues, including skeletal muscle. The development of medical technology has enabled the quantification of intramyocellular lipid (IMCL) content. IMCL levels may be regulated by the balance between lipid influx and its mitochondrial oxidation. Therefore, it is plausible that increased IMCL content is strongly associated with insulin resistance, possibly through excessive lipid overload accompanied by obesity and/or mitochondrial dysfunction due to aging and inherited abnormalities such as type 2 diabetes. However, it is known that trained athletes with high insulin sensitivity paradoxically display high levels of IMCL. Therefore, in addition to the quantity of IMCLs, lipid moieties (quality), including diacylglycerol, should be considered to discuss IMCLs and insulin resistance. Recent emerging evidence suggests that intramyocellular enzymes such as diacylglycerol acyltransferase 1 and stearoyl-CoA desaturase-1 can regulate muscle insulin sensitivity regardless of the amount of IMCLs. In this chapter, we focus on IMCLs and insulin resistance considering intramyocellular lipid moieties and insulin signaling.

Keywords

Intramyocellular lipid Insulin resistance Skeletal muscle Fatty acid 

References

  1. 1.
    Hocking S, Samocha-Bonet D, Milner KL, Greenfield JR, Chisholm DJ (2013) Adiposity and insulin resistance in humans: the role of the different tissue and cellular lipid depots. Endocr Rev 34:463–500. doi: 10.1210/er.2012-1041 CrossRefPubMedGoogle Scholar
  2. 2.
    Watt MJ, Hoy AJ (2012) Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function. Am J Physiol Endocrinol Metab 302:E1315–E1328. doi: 10.1152/ajpendo.00561.2011 CrossRefPubMedGoogle Scholar
  3. 3.
    Young SG, Zechner R (2013) Biochemistry and pathophysiology of intravascular and intracellular lipolysis. Genes Dev 27:459–484. doi: 10.1101/gad.209296.112 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Amati F, Dube JJ, Alvarez-Carnero E, Edreira MM, Chomentowski P, Coen PM et al (2011) Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes 60:2588–2597. doi: 10.2337/db10-1221 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Yokoyama H, Mori K, Emoto M, Araki T, Teramura M, Mochizuki K et al (2008) Non-oxidative glucose disposal is reduced in type 2 diabetes, but can be restored by aerobic exercise. Diabet Obes Metab 10:400–407. doi: 10.1111/j.1463-1326.2007.00716.x CrossRefGoogle Scholar
  6. 6.
    Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL et al (1999) Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42:113–116. doi: 10.1007/s001250051123 CrossRefPubMedGoogle Scholar
  7. 7.
    Perseghin G, Scifo P, De Cobelli F, Pagliato E, Battezzati A, Arcelloni C et al (1999) 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 48:1600–1606CrossRefPubMedGoogle Scholar
  8. 8.
    Tamura Y, Tanaka Y, Sato F, Choi JB, Watada H, Niwa M et al (2005) Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 90:3191–3196. doi: 10.1210/jc.2004-1959 CrossRefPubMedGoogle Scholar
  9. 9.
    Goodpaster BH, He J, Watkins S, Kelley DE (2001) Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab 86:5755–5761. doi: 10.1210/jcem.86.12.8075 CrossRefPubMedGoogle Scholar
  10. 10.
    Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1(7285):785–789CrossRefPubMedGoogle Scholar
  11. 11.
    Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW et al (1996) Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97:2859–2865. doi: 10.1172/JCI118742 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Samuel VT, Petersen KF, Shulman GI (2010) Lipid-induced insulin resistance: unraveling the mechanism. Lancet 375(9733):2267–2277. doi: 10.1016/S0140-6736(10)60408-4 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Shulman GI (2014) Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 371:1131–1141. doi: 10.1056/NEJMra1011035 CrossRefPubMedGoogle Scholar
  14. 14.
    Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW et al (1999) Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 103:253–259. doi: 10.1172/JCI5001 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Saini-Chohan HK, Mitchell RW, Vaz FM, Zelinski T, Hatch GM (2012) Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders: thematic review series: genetics of human lipid diseases. J Lipid Res 53:4–27. doi: 10.1194/jlr.R012120 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Stannard SR, Johnson NA (2004) Insulin resistance and elevated triglyceride in muscle: more important for survival than “thrifty” genes? J Physiol 554:595–607. doi: 10.1113/jphysiol.2003.053926 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Liu L, Zhang Y, Chen N, Shi X, Tsang B, Yu YH (2007) Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J Clin Invest 117:1679–1689. doi: 10.1172/JCI30565 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Schenk S, Horowitz JF (2007) Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. J Clin Invest 117:1690–1698. doi: 10.1172/JCI30566 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chen HC, Jensen DR, Myers HM, Eckel RH, Farese RV Jr (2003) Obesity resistance and enhanced glucose metabolism in mice transplanted with white adipose tissue lacking acyl CoA: diacylglycerol acyltransferase 1. J Clin Invest 111:1715–1722. doi: 10.1172/JCI15859 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kusunoki J, Kanatani A, Moller DE (2006) Modulation of fatty acid metabolism as a potential approach to the treatment of obesity and the metabolic syndrome. Endocrine 29:91–100. doi: 10.1385/ENDO:29:1:91 CrossRefPubMedGoogle Scholar
  21. 21.
    Stamatikos AD, Paton CM (2013) Role of stearoyl-CoA desaturase-1 in skeletal muscle function and metabolism. Am J Physiol Endocrinol Metab 305:E767–E775. doi: 10.1152/ajpendo.00268.2013 CrossRefPubMedGoogle Scholar
  22. 22.
    Nolan CJ, Larter CZ (2009) Lipotoxicity: why do saturated fatty acids cause and monounsaturates protect against it? J Gastroenterol Hepatol 24:703–706. doi: 10.1111/j.1440-1746.2009.05823.x CrossRefPubMedGoogle Scholar
  23. 23.
    Hunnicutt JW, Hardy RW, Williford J, McDonald JM (1994) Saturated fatty acid-induced insulin resistance in rat adipocytes. Diabetes 43:540–545CrossRefPubMedGoogle Scholar
  24. 24.
    Rahman SM, Dobrzyn A, Dobrzyn P, Lee SH, Miyazaki M, Ntambi JM (2003) Stearoyl-CoA desaturase 1 deficiency elevates insulin-signaling components and down-regulates protein-tyrosine phosphatase 1B in muscle. Proc Natl Acad Sci U S A 100:11110–11115. doi: 10.1073/pnas.1934571100 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Dobrzyn P, Jazurek M, Dobrzyn A (1797) Stearoyl-CoA desaturase and insulin signaling – what is the molecular switch? Biochim Biophys Acta 2010:1189–1194. doi: 10.1016/j.bbabio.2010.02.007 Google Scholar
  26. 26.
    Newton AC (2003) Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm. Biochem J 370:361–371. doi: 10.1042/BJ20021626 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Dries DR, Gallegos LL, Newton AC (2007) A single residue in the C1 domain sensitizes novel protein kinase C isoforms to cellular diacylglycerol production. J Biol Chem 282:826–830. doi: 10.1074/jbc.C600268200 CrossRefPubMedGoogle Scholar
  28. 28.
    Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D et al (1999) Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 48:1270–1274CrossRefPubMedGoogle Scholar
  29. 29.
    Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y et al (2002) 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 277:50230–50236. doi: 10.1074/jbc.M200958200 CrossRefPubMedGoogle Scholar
  30. 30.
    Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, Kim DW et al (2004) PKC-theta knockout mice are protected from fat-induced insulin resistance. J Clin Invest 114:823–827. doi: 10.1172/JCI22230 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Morino K, Neschen S, Bilz S, Sono S, Tsirigotis D, Reznick RM et al (2008) Muscle-specific IRS-1 Ser->Ala transgenic mice are protected from fat-induced insulin resistance in skeletal muscle. Diabetes 57:2644–2651. doi: 10.2337/db06-0454 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Szendroedi J, Yoshimura T, Phielix E, Koliaki C, Marcucci M, Zhang D et al (2014) Role of diacylglycerol activation of PKCtheta in lipid-induced muscle insulin resistance in humans. Proc Natl Acad Sci U S A 111:9597–9602. doi: 10.1073/pnas.1409229111 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL et al (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300:1140–1142. doi: 10.1126/science.1082889 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671. doi: 10.1056/NEJMoa031314 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Befroy DE, Petersen KF, Dufour S, Mason GF, de Graaf RA, Rothman DL et al (2007) Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 56:1376–1381. doi: 10.2337/db06-0783 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Coen PM, Hames KC, Leachman EM, DeLany JP, Ritov VB, Menshikova EV et al (2013) Reduced skeletal muscle oxidative capacity and elevated ceramide but not diacylglycerol content in severe obesity. Obesity 21:2362–2371. doi: 10.1002/oby.20381 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Hannun YA, Obeid LM (2011) Many ceramides. J Biol Chem 286:27855–27862. doi: 10.1074/jbc.R111.254359 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  • Katsuhito Mori
    • 1
    Email author
  • Tomoaki Morioka
    • 1
  • Koka Motoyama
    • 1
  • Masanori Emoto
    • 1
  1. 1.The Department of Metabolism, Endocrinology and Molecular MedicineOsaka City University Graduate School of MedicineOsakaJapan

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