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Insulin resistance in obesity: an overview of fundamental alterations

Abstract

Obesity is a major health risk factor, and obesity-induced morbidity and complications account for huge costs for affected individuals, families, healthcare systems, and society at large. In particular, obesity is strongly associated with the development of insulin resistance, which in turn plays a key role in the pathogenesis of obesity-associated cardiometabolic complications, including metabolic syndrome components, type 2 diabetes, and cardiovascular diseases. Insulin sensitive tissues, including adipose tissue, skeletal muscle, and liver, are profoundly affected by obesity both at biomolecular and functional levels. Altered adipose organ function may play a fundamental pathogenetic role once fat accumulation has ensued. Modulation of insulin sensitivity appears to be, at least in part, related to changes in redox balance and oxidative stress as well as inflammation, with a relevant underlying role for mitochondrial dysfunction that may exacerbate these alterations. Nutrients and substrates as well as systems involved in host–nutrient interactions, including gut microbiota, have been also identified as modulators of metabolic pathways controlling insulin action. This review aims at providing an overview of these concepts and their potential inter-relationships in the development of insulin resistance, with particular regard to changes in adipose organ and skeletal muscle.

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References

  1. Barazzoni R, Zanetti M, Gortan Cappellari G, Semolic A, Boschelle M, Codarin E, Pirulli A, Cattin L, Guarnieri G (2012) Fatty acids acutely enhance insulin-induced oxidative stress and cause insulin resistance by increasing mitochondrial reactive oxygen species (ROS) generation and nuclear factor-kappaB inhibitor (IkappaB)-nuclear factor-kappaB (NFkappaB) activation in rat muscle, in the absence of mitochondrial dysfunction. Diabetologia 55(3):773–782. https://doi.org/10.1007/s00125-011-2396-x

    CAS  Article  PubMed  Google Scholar 

  2. Breen DM, Giacca A (2011) Effects of insulin on the vasculature. Curr Vasc Pharmacol 9(3):321–332

    CAS  Article  Google Scholar 

  3. Goldstein BJ, Mahadev K, Wu X (2005) Redox paradox: insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets. Diabetes 54(2):311–321

    CAS  Article  Google Scholar 

  4. Chen M, Porte D Jr (1976) The effect of rate and dose of glucose infusion on the acute insulin response in man. J Clin Endocrinol Metab 42(6):1168–1175. https://doi.org/10.1210/jcem-42-6-1168

    CAS  Article  PubMed  Google Scholar 

  5. Wilcox G (2005) Insulin and insulin resistance. Clin Biochem Rev 26(2):19–39

    PubMed  PubMed Central  Google Scholar 

  6. Draznin B, Rizza R (1997) Clinical research in diabetes and obesity. Contemporary biomedicine. Humana Press, Totowa

    Book  Google Scholar 

  7. Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS (2003) Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci USA 100(13):7996–8001. https://doi.org/10.1073/pnas.1332551100

    CAS  Article  PubMed  Google Scholar 

  8. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS (2007) Regulation of lipolysis in adipocytes. Annu Rev Nutr 27:79–101. https://doi.org/10.1146/annurev.nutr.27.061406.093734

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Luzi L, Petrides AS, De Fronzo RA (1993) Different sensitivity of glucose and amino acid metabolism to insulin in NIDDM. Diabetes 42(12):1868–1877

    CAS  Article  Google Scholar 

  10. Williams KJ, Wu X (2016) Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward. Atherosclerosis 247:225–282. https://doi.org/10.1016/j.atherosclerosis.2016.02.004

    CAS  Article  PubMed  Google Scholar 

  11. Popkin BM, Adair LS, Ng SW (2012) Global nutrition transition and the pandemic of obesity in developing countries. Nutr Rev 70(1):3–21. https://doi.org/10.1111/j.1753-4887.2011.00456.x

    Article  PubMed  PubMed Central  Google Scholar 

  12. American Medical Association House of Delegates (2013) Resolution 420 (A-13). http://www.npr.org/documents/2013/jun/ama-resolution-obesity.pdf. Accessed 19 Jan 2018

  13. Pataky Z, Bobbioni-Harsch E, Golay A (2010) Open questions about metabolically normal obesity. Int J Obes (Lond) 34(Suppl 2):S18-23. https://doi.org/10.1038/ijo.2010.235

    Article  Google Scholar 

  14. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120(16):1640–1645. https://doi.org/10.1161/CIRCULATIONAHA.109.192644

    CAS  Article  PubMed  Google Scholar 

  15. 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(4):463–500. https://doi.org/10.1210/er.2012-1041

    CAS  Article  PubMed  Google Scholar 

  16. Sethi JK, Vidal-Puig AJ (2007) Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res 48(6):1253–1262. https://doi.org/10.1194/jlr.R700005-JLR200

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Gortan Cappellari G, Semolic A, Ruozi G, Vinci P, Guarnieri G, Bortolotti F, Barbetta D, Zanetti M, Giacca M, Barazzoni R (2017) Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease. Faseb J. https://doi.org/10.1096/fj.201700126R

    Article  PubMed  Google Scholar 

  18. Gortan Cappellari G, Zanetti M, Semolic A, Vinci P, Ruozi G, Falcione A, Filigheddu N, Guarnieri G, Graziani A, Giacca M, Barazzoni R (2016) Unacylated ghrelin reduces skeletal muscle reactive oxygen species generation and inflammation and prevents high-fat diet-induced hyperglycemia and whole-body insulin resistance in rodents. Diabetes 65(4):874–886. https://doi.org/10.2337/db15-1019

    CAS  Article  PubMed  Google Scholar 

  19. Barazzoni R, Zanetti M, Nagliati C, Cattin MR, Ferreira C, Giuricin M, Palmisano S, Edalucci E, Dore F, Guarnieri G, de Manzini N (2013) Gastric bypass does not normalize obesity-related changes in ghrelin profile and leads to higher acylated ghrelin fraction. Obesity (Silver Spring) 21(4):718–722. https://doi.org/10.1002/oby.20272

    CAS  Article  Google Scholar 

  20. Barazzoni R, Zanetti M, Stulle M, Mucci MP, Pirulli A, Dore F, Panzetta G, Vasile A, Biolo G, Guarnieri G (2008) Higher total ghrelin levels are associated with higher insulin-mediated glucose disposal in non-diabetic maintenance hemodialysis patients. Clin Nutr 27(1):142–149. https://doi.org/10.1016/j.clnu.2007.06.013

    CAS  Article  PubMed  Google Scholar 

  21. Birnbaum MJ (2001) Turning down insulin signaling. J Clin Invest 108(5):655–659. https://doi.org/10.1172/JCI13714

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108(3):437–446. https://doi.org/10.1172/JCI11559

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116(7):1793–1801. https://doi.org/10.1172/JCI29069

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Zanetti M, Barazzoni R, Guarnieri G (2008) Inflammation and insulin resistance in uremia. J Ren Nutr 18(1):70–75. https://doi.org/10.1053/j.jrn.2007.10.015

    Article  PubMed  Google Scholar 

  25. Anderson EJ, Lustig ME, Boyle KE, Woodlief TL, Kane DA, Lin CT, Price JW 3rd, Kang L, Rabinovitch PS, Szeto HH, Houmard JA, Cortright RN, Wasserman DH, Neufer PD (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):573–581. https://doi.org/10.1172/JCI37048

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Rani V, Deep G, Singh RK, Palle K, Yadav UC (2016) Oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies. Life Sci 148:183–193. https://doi.org/10.1016/j.lfs.2016.02.002

    CAS  Article  PubMed  Google Scholar 

  27. Barazzoni R, Gortan Cappellari G, Palus S, Vinci P, Ruozi G, Zanetti M, Semolic A, Ebner N, von Heahling S, Sinagra G, Giacca M, Springer J (2017) Acylated ghrelin treatment normalizes skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rat chronic heart failure. J Cachexia Sarcopenia Muscle. https://doi.org/10.1002/jcsm.12254

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bifari F, Ruocco C, Decimo I, Fumagalli G, Valerio A, Nisoli E (2017) Amino acid supplements and metabolic health: a potential interplay between intestinal microbiota and systems control. Genes Nutr 12:27. https://doi.org/10.1186/s12263-017-0582-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W, Pettersson S (2012) Host-gut microbiota metabolic interactions. Science 336(6086):1262–1267. https://doi.org/10.1126/science.1223813

    CAS  Article  PubMed  Google Scholar 

  30. Poulos SP, Hausman DB, Hausman GJ (2010) The development and endocrine functions of adipose tissue. Mol Cell Endocrinol 323(1):20–34. https://doi.org/10.1016/j.mce.2009.12.011

    CAS  Article  PubMed  Google Scholar 

  31. 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 (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8(11):1288–1295. https://doi.org/10.1038/nm788

    CAS  Article  PubMed  Google Scholar 

  32. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116(7):1784–1792. https://doi.org/10.1172/JCI29126

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB (1995) The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest 95(5):2111–2119. https://doi.org/10.1172/JCI117899

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G (2003) Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 52(7):1779–1785

    CAS  Article  Google Scholar 

  35. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114(12):1752–1761. https://doi.org/10.1172/JCI21625

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Barazzoni R, Bernardi A, Biasia F, Semolic A, Bosutti A, Mucci M, Dore F, Zanetti M, Guarnieri G (2007) Low fat adiponectin expression is associated with oxidative stress in nondiabetic humans with chronic kidney disease—impact on plasma adiponectin concentration. Am J Physiol Regul Integr Comp Physiol 293(1):R47-54. https://doi.org/10.1152/ajpregu.00745.2006

    CAS  Article  PubMed  Google Scholar 

  37. Marseglia L, Manti S, D’Angelo G, Nicotera A, Parisi E, Di Rosa G, Gitto E, Arrigo T (2014) Oxidative stress in obesity: a critical component in human diseases. Int J Mol Sci 16(1):378–400. https://doi.org/10.3390/ijms16010378

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Gomez-Serrano M, Camafeita E, Lopez JA, Rubio MA, Breton I, Garcia-Consuegra I, Garcia-Santos E, Lago J, Sanchez-Pernaute A, Torres A, Vazquez J, Peral B (2017) Differential proteomic and oxidative profiles unveil dysfunctional protein import to adipocyte mitochondria in obesity-associated aging and diabetes. Redox Biol 11:415–428. https://doi.org/10.1016/j.redox.2016.12.013

    CAS  Article  PubMed  Google Scholar 

  39. Pepping JK, Freeman LR, Gupta S, Keller JN, Bruce-Keller AJ (2013) NOX2 deficiency attenuates markers of adiposopathy and brain injury induced by high-fat diet. Am J Physiol Endocrinol Metab 304(4):E392-404. https://doi.org/10.1152/ajpendo.00398.2012

    CAS  Article  PubMed  Google Scholar 

  40. Gustafson B, Hedjazifar S, Gogg S, Hammarstedt A, Smith U (2015) Insulin resistance and impaired adipogenesis. Trends Endocrinol Metab 26(4):193–200. https://doi.org/10.1016/j.tem.2015.01.006

    CAS  Article  PubMed  Google Scholar 

  41. Giordano A, Murano I, Mondini E, Perugini J, Smorlesi A, Severi I, Barazzoni R, Scherer PE, Cinti S (2013) Obese adipocytes show ultrastructural features of stressed cells and die of pyroptosis. J Lipid Res 54(9):2423–2436. https://doi.org/10.1194/jlr.M038638

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Giordano A, Smorlesi A, Frontini A, Barbatelli G, Cinti S (2014) White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ. Eur J Endocrinol 170(5):R159-171. https://doi.org/10.1530/EJE-13-0945

    CAS  Article  Google Scholar 

  43. Kuo FC, Huang YH, Lin FH, Hung YJ, Hsieh CH, Lu CH, Su SC, Huang CL, Lee CH, Chu NF (2017) Circulating soluble IL-6 receptor concentration and visceral adipocyte size are related to insulin resistance in Taiwanese adults with morbid obesity. Metab Syndr Relat Disord 15(4):187–193. https://doi.org/10.1089/met.2016.0135

    CAS  Article  PubMed  Google Scholar 

  44. Weyer C, Foley JE, Bogardus C, Tataranni PA, Pratley RE (2000) Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 43(12):1498–1506. https://doi.org/10.1007/s001250051560

    CAS  Article  PubMed  Google Scholar 

  45. Eldor R, DeFronzo RA, Abdul-Ghani M (2013) In vivo actions of peroxisome proliferator-activated receptors: glycemic control, insulin sensitivity, and insulin secretion. Diabetes Care 36(Suppl 2):S162-174. https://doi.org/10.2337/dcS13-2003

    CAS  Article  Google Scholar 

  46. Cohen P, Spiegelman BM (2015) Brown and beige fat: molecular parts of a thermogenic machine. Diabetes 64(7):2346–2351. https://doi.org/10.2337/db15-0318

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Giordano A, Frontini A, Cinti S (2016) Convertible visceral fat as a therapeutic target to curb obesity. Nat Rev Drug Discov 15(6):405–424. https://doi.org/10.1038/nrd.2016.31

    CAS  Article  PubMed  Google Scholar 

  48. Martinez-Sanchez N, Moreno-Navarrete JM, Contreras C, Rial-Pensado E, Ferno J, Nogueiras R, Dieguez C, Fernandez-Real JM, Lopez M (2017) Thyroid hormones induce browning of white fat. J Endocrinol 232(2):351–362. https://doi.org/10.1530/JOE-16-0425

    CAS  Article  PubMed  Google Scholar 

  49. Weiner J, Kranz M, Kloting N, Kunath A, Steinhoff K, Rijntjes E, Kohrle J, Zeisig V, Hankir M, Gebhardt C, Deuther-Conrad W, Heiker JT, Kralisch S, Stumvoll M, Bluher M, Sabri O, Hesse S, Brust P, Tonjes A, Krause K (2016) Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice. Sci Rep 6:38124. https://doi.org/10.1038/srep38124

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Ramage LE, Akyol M, Fletcher AM, Forsythe J, Nixon M, Carter RN, van Beek EJ, Morton NM, Walker BR, Stimson RH (2016) Glucocorticoids acutely increase brown adipose tissue activity in humans, revealing species-specific differences in UCP-1 regulation. Cell Metab 24(1):130–141. https://doi.org/10.1016/j.cmet.2016.06.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. Kong X, Yu J, Bi J, Qi H, Di W, Wu L, Wang L, Zha J, Lv S, Zhang F, Li Y, Hu F, Liu F, Zhou H, Liu J, Ding G (2015) Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue. Diabetes 64(2):393–404. https://doi.org/10.2337/db14-0395

    CAS  Article  PubMed  Google Scholar 

  52. Trayhurn P (2016) Recruiting brown adipose tissue in human obesity. Diabetes 65(5):1158–1160. https://doi.org/10.2337/dbi16-0002

    CAS  Article  PubMed  Google Scholar 

  53. Yuan X, Wei G, You Y, Huang Y, Lee HJ, Dong M, Lin J, Hu T, Zhang H, Zhang C, Zhou H, Ye R, Qi X, Zhai B, Huang W, Liu S, Xie W, Liu Q, Liu X, Cui C, Li D, Zhan J, Cheng J, Yuan Z, Jin W (2017) Rutin ameliorates obesity through brown fat activation. Faseb J 31(1):333–345. https://doi.org/10.1096/fj.201600459RR

    CAS  Article  PubMed  Google Scholar 

  54. Bonnard C, Durand A, Peyrol S, Chanseaume E, Chauvin MA, Morio B, Vidal H, Rieusset J (2008) Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 118(2):789–800. https://doi.org/10.1172/JCI32601

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Valerio A, Cardile A, Cozzi V, Bracale R, Tedesco L, Pisconti A, Palomba L, Cantoni O, Clementi E, Moncada S, Carruba MO, Nisoli E (2006) TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. J Clin Invest 116(10):2791–2798. https://doi.org/10.1172/JCI28570

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Boden G (2011) Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes 18(2):139–143. https://doi.org/10.1097/MED.0b013e3283444b09

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Boden G, Chen X (1995) Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest 96(3):1261–1268. https://doi.org/10.1172/JCI118160

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Boden G, Jadali F, White J, Liang Y, Mozzoli M, Chen X, Coleman E, Smith C (1991) Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. J Clin Invest 88(3):960–966. https://doi.org/10.1172/JCI115399

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Mittendorfer B (2011) Origins of metabolic complications in obesity: adipose tissue and free fatty acid trafficking. Curr Opin Clin Nutr Metab Care 14(6):535–541. https://doi.org/10.1097/MCO.0b013e32834ad8b6

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Paolisso G, Gambardella A, Tagliamonte MR, Saccomanno F, Salvatore T, Gualdiero P, D’Onofrio MV, Howard BV (1996) Does free fatty acid infusion impair insulin action also through an increase in oxidative stress? J Clin Endocrinol Metab 81(12):4244–4248. https://doi.org/10.1210/jcem.81.12.8954022

    CAS  Article  PubMed  Google Scholar 

  61. Guo W, Wong S, Xie W, Lei T, Luo Z (2007) Palmitate modulates intracellular signaling, induces endoplasmic reticulum stress, and causes apoptosis in mouse 3T3-L1 and rat primary preadipocytes. Am J Physiol Endocrinol Metab 293(2):E576-586. https://doi.org/10.1152/ajpendo.00523.2006

    CAS  Article  Google Scholar 

  62. Rachek LI, Musiyenko SI, LeDoux SP, Wilson GL (2007) Palmitate induced mitochondrial deoxyribonucleic acid damage and apoptosis in l6 rat skeletal muscle cells. Endocrinology 148(1):293–299. https://doi.org/10.1210/en.2006-0998

    CAS  Article  PubMed  Google Scholar 

  63. Yuzefovych L, Wilson G, Rachek L (2010) Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress. Am J Physiol Endocrinol Metab 299(6):E1096-1105. https://doi.org/10.1152/ajpendo.00238.2010

    CAS  Article  Google Scholar 

  64. Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA, Jenkinson CP, Mandarino LJ (2005) Lipid infusion decreases the expression of nuclear encoded mitochondrial genes and increases the expression of extracellular matrix genes in human skeletal muscle. J Biol Chem 280(11):10290–10297. https://doi.org/10.1074/jbc.M408985200

    CAS  Article  PubMed  Google Scholar 

  65. Samuel VT, Petersen KF, Shulman GI (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet 375(9733):2267–2277. https://doi.org/10.1016/S0140-6736(10)60408-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Shulman GI (2014) Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 371(23):2237–2238. https://doi.org/10.1056/NEJMc1412427

    Article  PubMed  Google Scholar 

  67. Guarnieri G, Zanetti M, Vinci P, Cattin MR, Barazzoni R (2009) Insulin resistance in chronic uremia. J Ren Nutr 19(1):20–24. https://doi.org/10.1053/j.jrn.2008.11.014

    CAS  Article  PubMed  Google Scholar 

  68. Bikman BT, Summers SA (2011) Ceramides as modulators of cellular and whole-body metabolism. J Clin Invest 121(11):4222–4230. https://doi.org/10.1172/JCI57144

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Ritter O, Jelenik T, Roden M (2015) Lipid-mediated muscle insulin resistance: different fat, different pathways? J Mol Med (Berl) 93(8):831–843. https://doi.org/10.1007/s00109-015-1310-2

    CAS  Article  Google Scholar 

  70. Jans A, Konings E, Goossens GH, Bouwman FG, Moors CC, Boekschoten MV, Afman LA, Muller M, Mariman EC, Blaak EE (2012) PUFAs acutely affect triacylglycerol-derived skeletal muscle fatty acid uptake and increase postprandial insulin sensitivity. Am J Clin Nutr 95(4):825–836. https://doi.org/10.3945/ajcn.111.028787

    CAS  Article  PubMed  Google Scholar 

  71. Storlien LH, Baur LA, Kriketos AD, Pan DA, Cooney GJ, Jenkins AB, Calvert GD, Campbell LV (1996) Dietary fats and insulin action. Diabetologia 39(6):621–631

    CAS  Article  Google Scholar 

  72. Barazzoni R, Gortan Cappellari G, Semolic A, Ius M, Dore F, Giacca M, Zanetti M, Vinci P, Guarnieri G (2017) Intravenous lipid infusion and total plasma fatty acids positively modulate plasma acylated ghrelin in vivo. Clin Nutr 36(3):775–781. https://doi.org/10.1016/j.clnu.2016.05.017

    CAS  Article  PubMed  Google Scholar 

  73. Bravard A, Bonnard C, Durand A, Chauvin MA, Favier R, Vidal H, Rieusset J (2011) Inhibition of xanthine oxidase reduces hyperglycemia-induced oxidative stress and improves mitochondrial alterations in skeletal muscle of diabetic mice. Am J Physiol Endocrinol Metab 300(3):E581-591. https://doi.org/10.1152/ajpendo.00455.2010

    CAS  Article  Google Scholar 

  74. Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55(Suppl 2):S9-S15. https://doi.org/10.2337/db06-S002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. Barazzoni R, Zanetti M, Semolic A, Cattin MR, Pirulli A, Cattin L, Guarnieri G (2011) High-fat diet with acyl-ghrelin treatment leads to weight gain with low inflammation, high oxidative capacity and normal triglycerides in rat muscle. PLoS One 6(10):e26224. https://doi.org/10.1371/journal.pone.0026224

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Barazzoni R (2004) Skeletal muscle mitochondrial protein metabolism and function in ageing and type 2 diabetes. Curr Opin Clin Nutr Metab Care 7(1):97–102

    CAS  Article  Google Scholar 

  77. Barazzoni R, Zanetti M, Bosutti A, Biolo G, Vitali-Serdoz L, Stebel M, Guarnieri G (2005) Moderate caloric restriction, but not physiological hyperleptinemia per se, enhances mitochondrial oxidative capacity in rat liver and skeletal muscle–tissue-specific impact on tissue triglyceride content and AKT activation. Endocrinology 146(4):2098–2106. https://doi.org/10.1210/en.2004-1396

    CAS  Article  PubMed  Google Scholar 

  78. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34(3):267–273. https://doi.org/10.1038/ng1180

    CAS  Article  PubMed  Google Scholar 

  79. Jheng HF, Huang SH, Kuo HM, Hughes MW, Tsai YS (2015) Molecular insight and pharmacological approaches targeting mitochondrial dynamics in skeletal muscle during obesity. Ann N Y Acad Sci 1350:82–94. https://doi.org/10.1111/nyas.12863

    Article  PubMed  Google Scholar 

  80. Bondia-Pons I, Ryan L, Martinez JA (2012) Oxidative stress and inflammation interactions in human obesity. J Physiol Biochem 68(4):701–711. https://doi.org/10.1007/s13105-012-0154-2

    CAS  Article  PubMed  Google Scholar 

  81. de Mello AH, Costa AB, Engel JDG, Rezin GT (2018) Mitochondrial dysfunction in obesity. Life Sci 192:26–32. https://doi.org/10.1016/j.lfs.2017.11.019

    CAS  Article  PubMed  Google Scholar 

  82. Chavez AO, Kamath S, Jani R, Sharma LK, Monroy A, Abdul-Ghani MA, Centonze VE, Sathyanarayana P, Coletta DK, Jenkinson CP, Bai Y, Folli F, Defronzo RA, Tripathy D (2010) Effect of short-term free Fatty acids elevation on mitochondrial function in skeletal muscle of healthy individuals. J Clin Endocrinol Metab 95(1):422–429. https://doi.org/10.1210/jc.2009-1387

    CAS  Article  PubMed  Google Scholar 

  83. Nair KS, Bigelow ML, Asmann YW, Chow LS, Coenen-Schimke JM, Klaus KA, Guo ZK, Sreekumar R, Irving BA (2008) Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes 57(5):1166–1175. https://doi.org/10.2337/db07-1556

    CAS  Article  PubMed  Google Scholar 

  84. Ostergard T, Andersen JL, Nyholm B, Lund S, Nair KS, Saltin B, Schmitz O (2006) Impact of exercise training on insulin sensitivity, physical fitness, and muscle oxidative capacity in first-degree relatives of type 2 diabetic patients. Am J Physiol Endocrinol Metab 290(5):E998-1005. https://doi.org/10.1152/ajpendo.00012.2005

    CAS  Article  PubMed  Google Scholar 

  85. Short KR, Vittone JL, Bigelow ML, Proctor DN, Rizza RA, Coenen-Schimke JM, Nair KS (2003) Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity. Diabetes 52(8):1888–1896

    CAS  Article  Google Scholar 

  86. Toledo FG, Menshikova EV, Azuma K, Radikova Z, Kelley CA, Ritov VB, Kelley DE (2008) Mitochondrial capacity in skeletal muscle is not stimulated by weight loss despite increases in insulin action and decreases in intramyocellular lipid content. Diabetes 57(4):987–994. https://doi.org/10.2337/db07-1429

    CAS  Article  PubMed  Google Scholar 

  87. Sarparanta J, Garcia-Macia M, Singh R (2016) Autophagy and mitochondria in obesity and type 2 diabetes. Curr Diabetes Rev 13(4):352–369. https://doi.org/10.2174/1573399812666160217122530

    CAS  Article  Google Scholar 

  88. Buchner DA, Yazbek SN, Solinas P, Burrage LC, Morgan MG, Hoppel CL, Nadeau JH (2011) Increased mitochondrial oxidative phosphorylation in the liver is associated with obesity and insulin resistance. Obesity (Silver Spring) 19(5):917–924. https://doi.org/10.1038/oby.2010.214

    CAS  Article  Google Scholar 

  89. Takamura T, Misu H, Matsuzawa-Nagata N, Sakurai M, Ota T, Shimizu A, Kurita S, Takeshita Y, Ando H, Honda M, Kaneko S (2008) Obesity upregulates genes involved in oxidative phosphorylation in livers of diabetic patients. Obesity (Silver Spring) 16(12):2601–2609. https://doi.org/10.1038/oby.2008.419

    CAS  Article  Google Scholar 

  90. Cani PD, Delzenne NM (2007) Gut microflora as a target for energy and metabolic homeostasis. Curr Opin Clin Nutr Metab Care 10(6):729–734. https://doi.org/10.1097/MCO.0b013e3282efdebb

    Article  PubMed  Google Scholar 

  91. Cani PD, Delzenne NM (2009) The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 15(13):1546–1558

    CAS  Article  Google Scholar 

  92. Rowland I, Gibson G, Heinken A, Scott K, Swann J, Thiele I, Tuohy K (2017) Gut microbiota functions: metabolism of nutrients and other food components. Eur J Nutr. https://doi.org/10.1007/s00394-017-1445-8

    Article  PubMed  PubMed Central  Google Scholar 

  93. Cani PD (2014) Metabolism in 2013: the gut microbiota manages host metabolism. Nat Rev Endocrinol 10(2):74–76. https://doi.org/10.1038/nrendo.2013.240

    Article  PubMed  Google Scholar 

  94. Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, Almeida M, Arumugam M, Batto JM, Kennedy S, Leonard P, Li J, Burgdorf K, Grarup N, Jorgensen T, Brandslund I, Nielsen HB, Juncker AS, Bertalan M, Levenez F, Pons N, Rasmussen S, Sunagawa S, Tap J, Tims S, Zoetendal EG, Brunak S, Clement K, Dore J, Kleerebezem M, Kristiansen K, Renault P, Sicheritz-Ponten T, de Vos WM, Zucker JD, Raes J, Hansen T, Bork P, Wang J, Ehrlich SD, Pedersen O (2013) Richness of human gut microbiome correlates with metabolic markers. Nature 500(7464):541–546. https://doi.org/10.1038/nature12506

    CAS  Article  PubMed  Google Scholar 

  95. Tahrani AA, Bailey CJ, Del Prato S, Barnett AH (2011) Management of type 2 diabetes: new and future developments in treatment. Lancet 378(9786):182–197. https://doi.org/10.1016/S0140-6736(11)60207-9

    CAS  Article  PubMed  Google Scholar 

  96. Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, Almeida M, Quinquis B, Levenez F, Galleron N, Gougis S, Rizkalla S, Batto JM, Renault P, Dore J, Zucker JD, Clement K, Ehrlich SD (2013) Dietary intervention impact on gut microbial gene richness. Nature 500(7464):585–588. https://doi.org/10.1038/nature12480

    CAS  Article  PubMed  Google Scholar 

  97. Geurts L, Neyrinck AM, Delzenne NM, Knauf C, Cani PD (2014) Gut microbiota controls adipose tissue expansion, gut barrier and glucose metabolism: novel insights into molecular targets and interventions using prebiotics. Benef Microbes 5(1):3–17. https://doi.org/10.3920/BM2012.0065

    CAS  Article  PubMed  Google Scholar 

  98. Kimura I, Ozawa K, Inoue D, Imamura T, Kimura K, Maeda T, Terasawa K, Kashihara D, Hirano K, Tani T, Takahashi T, Miyauchi S, Shioi G, Inoue H, Tsujimoto G (2013) The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43. Nat Commun 4:1829. https://doi.org/10.1038/ncomms2852

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Rocco Barazzoni or Enzo Nisoli.

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Barazzoni, R., Gortan Cappellari, G., Ragni, M. et al. Insulin resistance in obesity: an overview of fundamental alterations. Eat Weight Disord 23, 149–157 (2018). https://doi.org/10.1007/s40519-018-0481-6

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Keywords

  • Obesity
  • Insulin resistance
  • Inflammation
  • Oxidative stress