Advertisement

Cytosolic lipid excess-induced mitochondrial dysfunction is the cause or effect of high fat diet-induced skeletal muscle insulin resistance: a molecular insight

  • Baishali Alok Jana
  • Pavan Kumar Chintamaneni
  • Praveen Thaggikuppe Krishnamurthy
  • Ashish Wadhwani
  • Suresh Kumar Mohankumar
Original Article
  • 6 Downloads

Abstract

Mitochondria play a central role in the energy homeostasis in eukaryotic cells by generating ATP via oxidative metabolism of nutrients. Excess lipid accumulation and impairments in mitochondrial function have been considered as putative mechanisms for the pathogenesis of skeletal muscle insulin resistance. Accumulation of lipids in tissues occurs due to either excessive fatty acid uptake, decreased fatty acid utilization or both. Consequently, elevated levels cytosolic lipid metabolites, triglycerides, diacylglycerol and ceramides have been demonstrated to adversely affect glucose homeostasis. Several recent studies indicate that reduced insulin-stimulated ATP synthesis and reduced expression of mitochondrial enzymes and PPAR-γ coactivator, in high fat feeding (lipid overload) are associated with insulin resistance. Despite the fact, few notable studies suggest mitochondrial dysfunction is prevalent in type 2 diabetes mellitus; it is still not clear whether the defects in mitochondrial function are the cause of insulin resistance or the consequential effects of insulin resistance itself. Thus, there is a growing interest in understanding the intricacies of mitochondrial function and its association with cytosolic lipid excess. This review therefore critically examines the molecular cascades linking cytosolic lipid excess and mitochondrial dysfunction in the pathogenesis of high fat diet-induced insulin resistance in skeletal muscle.

Graphical abstract

The sequential processes following the excess intake of high fat diet in skeletal muscle includes, accumulation of cytosolic fatty acids, increased production of reactive oxygen species, mutations and ageing, and decreased mitochondrial biogenesis. The consequent mitochondrial dysfunction is then leading to decreased β-oxidation, respiratory functions and glycolysis and increased glucolipotoxicity. These events collectively induce the insulin resistance in skeletal muscle.

Keywords

Cytosolic lipids Mitochondria Insulin resistance High fat diet Type 2 diabetes mellitus 

Notes

Author contributions

SKM conceived the idea, skeleton, draft editing and proof reading; BAC wrote the initial draft contributed to molecular mechanisms; PKC contributed to the pharmacology aspects and drafted graphical abstract; PTK and AW contributed to the editing and proof reading. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Corpeleijn E, Saris WH, Blaak EE (2009) Metabolic flexibility in the development of insulin resistance and type 2 diabetes: effects of lifestyle. Obes Rev 10(2):178–193CrossRefPubMedGoogle Scholar
  2. 2.
    Lark D, Fisher-Wellman K, Neufer P (2012) High-fat load: mechanism (s) of insulin resistance in skeletal muscle. Int J Obes Suppl 2:S31–S36CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Krebs M, Roden M (2004) Nutrient-induced insulin resistance in human skeletal muscle. Curr Med Chem 11(7):901–908CrossRefPubMedGoogle Scholar
  4. 4.
    Holland WL, Summers SA (2008) Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev 29(4):381–402CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Perseghin G 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(8):1600–1606CrossRefPubMedGoogle Scholar
  6. 6.
    Brehm A et al (2006) Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle. Diabetes 55(1):136–140CrossRefPubMedGoogle Scholar
  7. 7.
    Befroy DE et al (2007) Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes 56(5):1376–1381CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Krssak M et al (1999) Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 42(1):113–116CrossRefPubMedGoogle Scholar
  9. 9.
    Mogensen M et al (2007) Mitochondrial respiration is decreased in skeletal muscle of patients with type 2 diabetes. Diabetes 56(6):1592–1599CrossRefPubMedGoogle Scholar
  10. 10.
    Ashrafian H, Frenneaux MP, Opie LH (2007) Metabolic mechanisms in heart failure. Circulation 116(4):434–448CrossRefPubMedGoogle Scholar
  11. 11.
    Ren J et al (2010) Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. J Mol Med 88(10):993–1001CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wiederkehr A, Wollheim CB (2006) Minireview: implication of mitochondria in insulin secretion and action. Endocrinology 147(6):2643–2649CrossRefPubMedGoogle Scholar
  13. 13.
    Brownlee M, The pathobiology of diabetic complications: a unifying mechanism. diabetes, 2005. 54(6): p. 1615–1625Google Scholar
  14. 14.
    Holloszy JO (2013) “Deficiency” of mitochondria in muscle does not cause insulin resistance. Diabetes 62(4):1036–1040CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Liesa M, Shirihai OS (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 17(4):491–506CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Simoneau J-A, Kelley DE (1997) Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM. J Appl Physiol 83(1):166–171CrossRefPubMedGoogle Scholar
  17. 17.
    Petersen KF et al (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350(7):664–671CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Fisher-Wellman KH, Neufer PD (2012) Linking mitochondrial bioenergetics to insulin resistance via redox biology. Trends Endocrinol Metab 23(3):142–153CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Muoio DM, Neufer PD (2012) Lipid-induced mitochondrial stress and insulin action in muscle. Cell Metab 15(5):595–605CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hegarty B et al (2003) The role of intramuscular lipid in insulin resistance. Acta Physiol 178(4):373–383CrossRefGoogle Scholar
  21. 21.
    Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307(5708):384–387CrossRefPubMedGoogle Scholar
  22. 22.
    Montgomery MK, Turner N (2015) Mitochondrial dysfunction and insulin resistance: an update. Endocr Connect 4(1):R1–R15CrossRefPubMedGoogle Scholar
  23. 23.
    Frankenfield DC, Muth ER, Rowe WA (1998) The Harris-Benedict studies of human basal metabolism: history and limitations. J Am Diet Assoc 98(4):439–445CrossRefPubMedGoogle Scholar
  24. 24.
    Garland P, Newsholme E, Randle P (1962) Effect of fatty acids, ketone bodies, diabetes and starvation on pyruvate metabolism in rat heart and diaphragm muscle. Nature 195(4839):381CrossRefPubMedGoogle Scholar
  25. 25.
    Randle P et al (1963) The glucose fatty-acid cycle its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 281(7285):785–789CrossRefGoogle Scholar
  26. 26.
    Sugden MC, Holness MJ (2006) Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases. Arch Physiol Biochem 112(3):139–149CrossRefPubMedGoogle Scholar
  27. 27.
    Shulman GI (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106(2):171–176CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Erion DM, Shulman GI (2010) Diacylglycerol-mediated insulin resistance. Nat Med 16(4):400CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ritov VB et al (2005) Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 54(1):8–14CrossRefPubMedGoogle Scholar
  30. 30.
    Petersen KF, Dufour S, Shulman GI (2005) Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med 2(9):e233CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Sparks LM et al (2005) A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 54(7):1926–1933CrossRefPubMedGoogle Scholar
  32. 32.
    Lionetti L et al (2007) Skeletal muscle subsarcolemmal mitochondrial dysfunction in high-fat fed rats exhibiting impaired glucose homeostasis. Int J Obes 31(10):1596CrossRefGoogle Scholar
  33. 33.
    Muoio DM (2010) Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? Biochim Biophys Acta BBA 1801(3):281–288CrossRefPubMedGoogle Scholar
  34. 34.
    Bonnard C et al (2008) Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 118(2):789–800PubMedPubMedCentralGoogle Scholar
  35. 35.
    Hoeks J et al (2011) High fat diet-induced changes in mouse muscle mitochondrial phospholipids do not impair mitochondrial respiration despite insulin resistance. PLoS ONE 6(11):e27274CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Kraegen EW, Cooney GJ, Turner N (2008) Muscle insulin resistance: a case of fat overconsumption, not mitochondrial dysfunction. Proc Natl Acad Sci USA 105(22):7627–7628CrossRefPubMedGoogle Scholar
  37. 37.
    Laurens C et al (2016) Perilipin 5 fine-tunes lipid oxidation to metabolic demand and protects against lipotoxicity in skeletal muscle. Sci Rep 6:38310CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Mason RR et al (2014) PLIN5 deletion remodels intracellular lipid composition and causes insulin resistance in muscle. Mol Metab 3(6):652–663CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Li X et al (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6(1):19CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Simoneau J-a et al (1999) Markers of capacity to utilize fatty acids in human skeletal muscle: relation to insulin resistance and obesity and effects of weight loss. FASEB J 13(14):2051–2060CrossRefPubMedGoogle Scholar
  41. 41.
    Lee K-U et al (2005) Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis. Circ Res 96(11):1200–1207CrossRefPubMedGoogle Scholar
  42. 42.
    Clapham JC et al (2000) Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406(6794):415CrossRefPubMedGoogle Scholar
  43. 43.
    Hulver MW et al (2003) Skeletal muscle lipid metabolism with obesity. Am J Physiol Endocrinol Metab 284(4):E741–E747CrossRefPubMedGoogle Scholar
  44. 44.
    Kelley DE et al (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51(10):2944–2950CrossRefPubMedGoogle Scholar
  45. 45.
    Kim J-Y et al (2000) Lipid oxidation is reduced in obese human skeletal muscle. Am J Physiol Endocrinol Metab 279(5):E1039–E1044CrossRefPubMedGoogle Scholar
  46. 46.
    Noland RC et al (2003) Acute endurance exercise increases skeletal muscle uncoupling protein-3 gene expression in untrained but not trained humans. Metabolism 52(2):152–158CrossRefPubMedGoogle Scholar
  47. 47.
    Simoneau J et al (1995) Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women. FASEB J 9(2):273–278CrossRefPubMedGoogle Scholar
  48. 48.
    Roden M (2005) Muscle triglycerides and mitochondrial function: possible mechanisms for the development of type 2 diabetes. Int J Obes 29(S2):S111CrossRefGoogle Scholar
  49. 49.
    Petersen KF et al (2003) Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 300(5622):1140–1142CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hancock CR et al (2008) High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci USA 105(22):7815–7820CrossRefPubMedGoogle Scholar
  51. 51.
    Koves TR et al (2005) Peroxisome proliferator-activated receptor-γ co-activator 1α-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem 280(39):33588–33598CrossRefPubMedGoogle Scholar
  52. 52.
    Koves TR et al (2008) Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7(1):45–56CrossRefPubMedGoogle Scholar
  53. 53.
    Desvergne B et al (1998) The peroxisome proliferator-activated receptors at the cross-road of diet and hormonal signalling1. J Steroid Biochem Mol Biol 65(1–6):65–74CrossRefPubMedGoogle Scholar
  54. 54.
    Coll T et al (2010) Activation of peroxisome proliferator-activated receptor-δ by GW501516 prevents fatty acid-induced nuclear factor-κB activation and insulin resistance in skeletal muscle cells. Endocrinology 151(4):1560–1569CrossRefPubMedGoogle Scholar
  55. 55.
    Guetre-Millo M, Gervois P, Raspe E (2000) Peroxisome proliferatoractivated receptor a activators improve insulin sensitivity and reduce adrposity. J Biol Chem 275(16):638–642Google Scholar
  56. 56.
    Alvim RO et al (2015) General aspects of muscle glucose uptake. An Acad Bras Ciênc 87(1):351–368CrossRefPubMedGoogle Scholar
  57. 57.
    Katz A (2007) Modulation of glucose transport in skeletal muscle by reactive oxygen species. J Appl Physiol 102(4):1671–1676CrossRefPubMedGoogle Scholar
  58. 58.
    Hoeks J et al (2010) Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance. Diabetes 59(9):2117–2125CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Westermann B (2012) Bioenergetic role of mitochondrial fusion and fission. Biochim Biophys Acta BBA 1817(10):1833–1838CrossRefPubMedGoogle Scholar
  60. 60.
    Chan DC (2006) Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 22:79–99CrossRefPubMedGoogle Scholar
  61. 61.
    Suen D-F, Norris KL, Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes Dev 22(12):1577–1590CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Detmer SA, Chan DC (2007) Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol 8(11):870CrossRefPubMedGoogle Scholar
  63. 63.
    Jheng H-F et al (2012) Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol 32(2):309–319CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Liu R et al (2014) Impaired mitochondrial dynamics and bioenergetics in diabetic skeletal muscle. PLoS ONE 9(3):e92810CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Handschin C, Spiegelman BM (2006) Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev 27(7):728–735CrossRefPubMedGoogle Scholar
  66. 66.
    Puigserver P et al (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92(6):829–839CrossRefPubMedGoogle Scholar
  67. 67.
    Kirkwood TB (2005) Understanding the odd science of aging. Cell 120(4):437–447CrossRefPubMedGoogle Scholar
  68. 68.
    McCarroll SA et al (2004) Comparing genomic expression patterns across species identifies shared transcriptional profile in aging. Nat Genet 36(2):197CrossRefPubMedGoogle Scholar
  69. 69.
    Evans JL et al (2003) Are oxidative stress—activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes 52(1):1–8CrossRefPubMedGoogle Scholar
  70. 70.
    Chance B, Williams G (1956) The respiratory chain and oxidative phosphorylation. Adv Enzymol Relat Areas Mol Biol 17:65–134Google Scholar
  71. 71.
    Affourtit C (2016) Mitochondrial involvement in skeletal muscle insulin resistance: a case of imbalanced bioenergetics. Biochim Biophys Acta BBA 1857(10):1678–1693CrossRefPubMedGoogle Scholar
  72. 72.
    Anderson EJ et al (2009) Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. J Clin Invest 119(3):573–581CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Di Meo S, Iossa S, Venditti P (2017) Skeletal muscle insulin resistance: role of mitochondria and other ROS sources. J Endocrinol 233(1):R15–R42CrossRefPubMedGoogle Scholar
  74. 74.
    Anderson EJ, Yamazaki H, Neufer PD (2007) Induction of endogenous UCP3 suppresses mitochondrial oxidant emission during fatty-acid supported respiration. J Biol Chem 282(43):31257–31266CrossRefPubMedGoogle Scholar
  75. 75.
    Seifert EL et al (2010) Electron transport chain-dependent and-independent mechanisms of mitochondrial H2O2 emission during long-chain fatty acid oxidation. J Biol Chem 285(8):5748–5758CrossRefPubMedGoogle Scholar
  76. 76.
    Chen L et al (2008) Reduction of mitochondrial H2O2 by overexpressing peroxiredoxin 3 improves glucose tolerance in mice. Aging cell 7(6):866–878CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Strachan MW (2003) Insulin and cognitive function. Lancet 362(9392):1253CrossRefPubMedGoogle Scholar
  78. 78.
    Lautamäki R et al (2006) Insulin improves myocardial blood flow in patients with type 2 diabetes and coronary artery disease. Diabetes 55(2):511–516CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Baishali Alok Jana
    • 1
  • Pavan Kumar Chintamaneni
    • 2
  • Praveen Thaggikuppe Krishnamurthy
    • 2
  • Ashish Wadhwani
    • 1
  • Suresh Kumar Mohankumar
    • 3
  1. 1.Department of Pharmaceutical BiotechnologyJSS College of Pharmacy (A Constituent College of JSS Academy of Higher Education & Research, Mysuru, Karnataka, India)OotacamundIndia
  2. 2.Department of PharmacologyJSS College of Pharmacy (A Constituent College of JSS Academy of Higher Education & Research, Mysuru, Karnataka, India)OotacamundIndia
  3. 3.Department of Pharmacognosy & PhytopharmacyTIFAC CORE in Herbal Drugs, JSS College of Pharmacy (A Constituent College of JSS Academy of Higher Education & Research, Mysuru, Karnataka, India)OotacamundIndia

Personalised recommendations