Obesity in the Pathophysiology of Diabetes

  • Juan Antonio Paniagua González
  • Antonio Vidal-Puig


Obesity and overweight states are characterized by an excessive accumulation of body fat. Depending on the amount of fat accumulated, but also on the individual’s genetic and exposure to specific environmental factors, the obese patient can develop several health problems. The increase in the prevalence of obesity and associated complications is considered a major public health issue that affects all demographic groups, irrespective of age, sex, race, education, or economic level. The World Health Organization (WHO) estimates that more than 1.9 billion adults (≥18 years old) were overweight, and of these over 600 million were obese, according to worldwide data registered in 2014. In the United States, obesity rates have been rising in both, adults and children in recent years. The maintenance of a healthy weight, usually achieved between 18 and 25 years of age, requires a life-long sustained energy equilibrium between energy intake and energy expended, which is affected not only by diet but also age, stage of development, genetic makeup as well as epigenetic, level of nutritional education, as well as physical and psychosocial interactions.


Adipocytes Adipokines Mesenchymal stem cells Lipotoxicity syndrome Incretins β-Cell dysfunction β-Cell mass Pancreatic stem cells Embryonic T2D 


Author Contributions

Paniagua JA was responsible for drafting and finalizing the manuscript. JAP and A V-P were responsible for final approval.

Conflict-of-Interest Statement

The authors do not have potential conflict of interest.

Manuscript Source

Invited manuscript


  1. 1.
    Berghofer A, Pischon T, Reinhold T, Apovian CM, Sharma AM, Willich SN. Obesity prevalence from a European perspective: a systematic review. BMC Public Health. 2008;8:200.]. [PMID: 18533989 PMCID: 2441615].CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    World Health Organization. Obesity and overweight, WdU, 2016. UJ. Obesity and overweight, 2016. World Health Organization; 2016.
  3. 3.
    Engeland A, Bjorge T, Sogaard AJ, Tverdal A. Body mass index in adolescence in relation to total mortality: 32-year follow-up of 227,000 Norwegian boys and girls. Am J Epidemiol. 2003;157(6):517–23. [PMID: 12631541].PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA J Am Med Assoc. 2002;288(14):1723–7. [PMID: 12365955].CrossRefGoogle Scholar
  5. 5.
    Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960–1994. Int J Obes Relat Metab Disord: J Int Assoc Study Obes. 1998;22(1):39–47. [PMID: 9481598].CrossRefGoogle Scholar
  6. 6.
    Kopelman PG. Obesity as a medical problem. Nature. 2000;404(6778):635–43. [PMID: 10766250].CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. New Engl J Med. 2007;357(4):370–9. [PMID: 17652652].CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Eyre H, Kahn R, Robertson RM, Committee AAACW. Preventing cancer, cardiovascular disease, and diabetes: a common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association. CA Cancer J Clin. 2004;54(4):190–207. [PMID: 15253917].PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Pischon T, Boeing H, Hoffmann K, Bergmann M, Schulze MB, Overvad K, van der Schouw YT, Spencer E, Moons KG, Tjonneland A, Halkjaer J, Jensen MK, Stegger J, Clavel-Chapelon F, Boutron-Ruault MC, Chajes V, Linseisen J, Kaaks R, Trichopoulou A, Trichopoulos D, Bamia C, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, May AM, Bueno-de-Mesquita HB, van Duijnhoven FJ, Hallmans G, Weinehall L, Manjer J, Hedblad B, Lund E, Agudo A, Arriola L, Barricarte A, Navarro C, Martinez C, Quiros JR, Key T, Bingham S, Khaw KT, Boffetta P, Jenab M, Ferrari P, Riboli E. General and abdominal adiposity and risk of death in Europe. N Engl J Med. 2008;359(20):2105–20. [PMID: 19005195].CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, Moore SC, Tobias GS, Anton-Culver H, Freeman LB, Beeson WL, Clipp SL, English DR, Folsom AR, Freedman DM, Giles G, Hakansson N, Henderson KD, Hoffman-Bolton J, Hoppin JA, Koenig KL, Lee IM, Linet MS, Park Y, Pocobelli G, Schatzkin A, Sesso HD, Weiderpass E, Willcox BJ, Wolk A, Zeleniuch-Jacquotte A, Willett WC, Thun MJ. Body-mass index and mortality among 1.46 million white adults. N Engl J Med. 2010;363(23):2211–9. [PMID: 21121834 PMCID: 3066051].CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ezzati M, Riboli E. Behavioral and dietary risk factors for noncommunicable diseases. N Engl J Med. 2013;369(10):954–64. [PMID: 24004122].CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, D.C.: American Institute for Cancer Research; 2007.Google Scholar
  13. 13.
    Mozaffarian D, Appel LJ, Van Horn L. Components of a cardioprotective diet: new insights. Circulation. 2011;123(24):2870–91. [PMID: 21690503].CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    He FJ, Li J, Macgregor GA. Effect of longer term modest salt reduction on blood pressure: Cochrane systematic review and meta-analysis of randomised trials. BMJ. 2013;346:f1325. [PMID: 23558162].CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sacks FM, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, McManus K, Champagne CM, Bishop LM, Laranjo N, Leboff MS, Rood JC, de Jonge L, Greenway FL, Loria CM, Obarzanek E, Williamson DA. Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. N Engl J Med. 2009;360(9):859–73. [PMID: 19246357 PMCID: 2763382].CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med. 2011;364(25):2392–404. [PMID: 21696306 PMCID: 3151731].CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Manson JE, Willett WC, Stampfer MJ, Colditz GA, Hunter DJ, Hankinson SE, Hennekens CH, Speizer FE. Body weight and mortality among women. N Engl J Med. 1995;333(11):677–85. [PMID: 7637744].CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Willett WC, Manson JE, Stampfer MJ, Colditz GA, Rosner B, Speizer FE. Hennekens CH. Weight, weight change, and coronary heart disease in women. Risk within the ‘normal’ weight range. JAMA. 1995;273(6):461–5. [PMID: 7654270].PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Stevens J, Plankey MW, Williamson DF, Thun MJ, Rust PF, Palesch Y, O’Neil PM. The body mass index-mortality relationship in white and African American women. Obes Res. 1998;6(4):268–77. [PMID: 9688103].PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Lindsted KD, Singh PN. Body mass and 26 y risk of mortality among men who never smoked: a re-analysis among men from the Adventist Mortality Study. Int J Obes Relat Metab Disord J Int Assoc Study Obes. 1998;22(6):544–8. [PMID: 9665675].CrossRefGoogle Scholar
  21. 21.
    Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr. Body-mass index and mortality in a prospective cohort of U.S. adults. N Engl J Med. 1999;341(15):1097–105. [PMID: 10511607].CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Association AH. Heart disease and stroke statistics. Update Dallas: American Heart Association; 2004.Google Scholar
  23. 23.
    Association AH. Heart disease and stroke statistics. Update Dallas: American Heart Association; 2003.Google Scholar
  24. 24.
    Lew EA, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chronic Dis. 1979;32(8):563–76. [PMID: 468958].PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Kyrgiou M, Kalliala I, Markozannes G, Gunter MJ, Paraskevaidis E, Gabra H, Martin-Hirsch P, Tsilidis KK. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ. 2017;356:j477. [PMID: 28246088].CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–38. [PMID: 12711737].CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, Marks JS. Diabetes trends in the U.S.: 1990–1998. Diabetes Care. 2000;23(9):1278–83. [PMID: 10977060].PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes. 1999;48(5):937–42. [PMID: 10331395].PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Roglic G, Unwin N, Bennett PH, Mathers C, Tuomilehto J, Nag S, Connolly V, King H. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care. 2005;28(9):2130–5. [PMID: 16123478].PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Ford ES, Williamson DF, Liu S. Weight change and diabetes incidence: findings from a national cohort of US adults. Am J Epidemiol. 1997;146(3):214–22. [PMID: 9247005].PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Landin K, Krotkiewski M, Smith U. Importance of obesity for the metabolic abnormalities associated with an abdominal fat distribution. Metab Clin Exp. 1989;38(6):572–6. [PMID: 2657328].PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Peiris AN, Mueller RA, Smith GA, Struve MF, Kissebah AH. Splanchnic insulin metabolism in obesity. Influence of body fat distribution. J Clin Invest. 1986;78(6):1648–57. [PMID: 3537010 PMCID: 423938].CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hu FB, Manson JE, Stampfer MJ, Colditz G, Liu S, Solomon CG, Willett WC. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001;345(11):790–7. [PMID: 11556298].CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    American Diabetes A. (4) Foundations of care: education, nutrition, physical activity, smoking cessation, psychosocial care, and immunization. Diabetes Care. 2015;38(Suppl 1):S20–30. [PMID: 25537702].CrossRefGoogle Scholar
  35. 35.
    Kayikcioglu M, Ozdogan O. Nutrition and cardiovascular health: 2015 American Dietary Guidelines Advisory Report. Turk Kardiyoloji Dernegi arsivi: Turk Kardiyoloji Derneginin yayin organidir. 2015;43(8):667–72. [PMID: 26717326].CrossRefGoogle Scholar
  36. 36.
    Magnusson I, Rothman DL, Katz LD, Shulman RG, Shulman GI. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J Clin Invest. 1992;90(4):1323–7. [PMID: 1401068 PMCID: 443176].CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults–the evidence report. Obes Res. 1998;6(Suppl 2):51S–209S. [PMID: 9813653].Google Scholar
  38. 38.
    Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser. 1995;854:1–452. [PMID: 8594834].Google Scholar
  39. 39.
    Seidell JC, Flegal KM. Assessing obesity: classification and epidemiology. Br Med Bull. 1997;53(2):238–52. [PMID: 9246834].PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Wang J, Thornton JC, Kolesnik S, Pierson RN Jr. Anthropometry in body composition. An overview. Ann N Y Acad Sci. 2000;904:317–26. [PMID: 10865763].PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Ferland M, Despres JP, Tremblay A, Pinault S, Nadeau A, Moorjani S, Lupien PJ, Theriault G, Bouchard C. Assessment of adipose tissue distribution by computed axial tomography in obese women: association with body density and anthropometric measurements. Br J Nutr. 1989;61(2):139–48. [PMID: 2706220].PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Gomez JM, Heitmann BL, Kent-Smith L, Melchior JC, Pirlich M, Scharfetter H, Schols AM, Pichard C. Composition of the EWG. Bioelectrical impedance analysis–part I: review of principles and methods. Clin Nutr. 2004;23(5):1226–43. [PMID: 15380917].CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Deurenberg P, Weststrate JA, Seidell JC. Body mass index as a measure of body fatness: age- and sex-specific prediction formulas. Br J Nutr. 1991;65(2):105–14. [PMID: 2043597].PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Boggs DA, Rosenberg L, Cozier YC, Wise LA, Coogan PF, Ruiz-Narvaez EA, Palmer JR. General and abdominal obesity and risk of death among black women. N Engl J Med. 2011;365(10):901–8. [PMID: 21899451 PMCID: 3206314].CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Lean ME, Han TS, Morrison CE. Waist circumference as a measure for indicating need for weight management. BMJ. 1995;311(6998):158–61. [PMID: 7613427 PMCID: 2550221].PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr, International Diabetes Federation Task Force on E, Prevention, National Heart L, Blood I, American Heart A, World Heart F, International Atherosclerosis S, International Association for the Study of O. 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. 2009;120(16):1640–5. [PMID: 19805654].CrossRefGoogle Scholar
  47. 47.
    Ashwell M, Cole TJ, Dixon AK. Ratio of waist circumference to height is strong predictor of intra-abdominal fat. BMJ. 1996;313(7056):559–60. [PMID: 8790002 PMCID: 2351911].PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Cox BD, Whichelow M. Ratio of waist circumference to height is better predictor of death than body mass index. BMJ. 1996;313(7070):1487. [PMID: 8973270 PMCID: 2352984].PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Hsieh SD, Yoshinaga H. Waist/height ratio as a simple and useful predictor of coronary heart disease risk factors in women. Intern Med. 1995;34(12):1147–52. [PMID: 8929639].PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Vazquez G, Duval S, Jacobs DR Jr, Silventoinen K. Comparison of body mass index, waist circumference, and waist/hip ratio in predicting incident diabetes: a meta-analysis. Epidemiol Rev. 2007;29:115–28. [PMID: 17494056].CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Taylor RW, Jones IE, Williams SM, Goulding A. Evaluation of waist circumference, waist-to-hip ratio, and the conicity index as screening tools for high trunk fat mass, as measured by dual-energy X-ray absorptiometry, in children aged 3–19 y. Am J Clin Nutr. 2000;72(2):490–5. [PMID: 10919946].PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Paniagua JA, Gallego de la Sacristana A, Romero I, Vidal-Puig A, Latre JM, Sanchez E, Perez-Martinez P, Lopez-Miranda J, Perez-Jimenez F. Monounsaturated fat-rich diet prevents central body fat distribution and decreases postprandial adiponectin expression induced by a carbohydrate-rich diet in insulin-resistant subjects. Diabetes Care. 2007;30(7):1717–23. [PMID: 17384344].CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Shuster A, Patlas M, Pinthus JH, Mourtzakis M. The clinical importance of visceral adiposity: a critical review of methods for visceral adipose tissue analysis. Br J Radiol. 2012;85(1009):1–10. [PMID: 21937614 PMCID: 3473928].CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000;21(6):697–738. [PMID: 11133069].PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Hamilton G, Middleton MS, Bydder M, Yokoo T, Schwimmer JB, Kono Y, Patton HM, Lavine JE, Sirlin CB. Effect of PRESS and STEAM sequences on magnetic resonance spectroscopic liver fat quantification. J Magn Reson Imaging JMRI. 2009;30(1):145–52. [PMID: 19557733 PMCID: 2982807].CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Kim H, Taksali SE, Dufour S, Befroy D, Goodman TR, Petersen KF, Shulman GI, Caprio S, Constable RT. Comparative MR study of hepatic fat quantification using single-voxel proton spectroscopy, two-point dixon and three-point IDEAL. Magn Reson Med. 2008;59(3):521–7. [PMID: 18306404 PMCID: 2818363].CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Stern JH, Rutkowski JM, Scherer PE. Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk. Cell Metab. 2016;23(5):770–84. [PMID: 27166942 PMCID: 4864949].CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Naslund E, Britton T, Concha H, Hassan M, Ryden M, Frisen J, Arner P. Dynamics of fat cell turnover in humans. Nature. 2008;453(7196):783–7. [PMID: 18454136].CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Romere C, Duerrschmid C, Bournat J, Constable P, Jain M, Xia F, Saha PK, Del Solar M, Zhu B, York B, Sarkar P, Rendon DA, Gaber MW, LeMaire SA, Coselli JS, Milewicz DM, Sutton VR, Butte NF, Moore DD, Chopra AR. Asprosin, a fasting-induced glucogenic protein hormone. Cell. 2016;165(3):566–79. [PMID: 27087445 PMCID: 4852710].CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360(15):1500–8. [PMID: 19357405].CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360(15):1518–25. [PMID: 19357407].CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Lean ME. Brown adipose tissue in humans. Proc Nutr Soc. 1989;48(2):243–56. [PMID: 2678120].PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360(15):1509–17. [PMID: 19357406 PMCID: 2859951].CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Schulz TJ, Huang P, Huang TL, Xue R, McDougall LE, Townsend KL, Cypess AM, Mishina Y, Gussoni E, Tseng YH. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature. 2013;495(7441):379–83. [PMID: 23485971 PMCID: 3623555].CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Ouellet V, Routhier-Labadie A, Bellemare W, Lakhal-Chaieb L, Turcotte E, Carpentier AC, Richard D. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J Clin Endocrinol Metab. 2011;96(1):192–9. [PMID: 20943785].CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 2009;23(9):3113–20. [PMID: 19417078].CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Cypess AM, Kahn CR. The role and importance of brown adipose tissue in energy homeostasis. Curr Opin Pediatr. 2010;22(4):478–84. [PMID: 20489634 PMCID: 3593062].CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Cypess AM, White AP, Vernochet C, Schulz TJ, Xue R, Sass CA, Huang TL, Roberts-Toler C, Weiner LS, Sze C, Chacko AT, Deschamps LN, Herder LM, Truchan N, Glasgow AL, Holman AR, Gavrila A, Hasselgren PO, Mori MA, Molla M, Tseng YH. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat Med. 2013;19(5):635–9. [PMID: 23603815 PMCID: 3650129].CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Villarroya F, Cereijo R, Villarroya J, Giralt M. Brown adipose tissue as a secretory organ. Nat Rev Endocrinol. 2017;13(1):26–35. [PMID: 27616452].CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Cinti S. The adipose organ at a glance. Dis Model Mech. 2012;5(5):588–94. [PMID: 22915020 PMCID: 3424455].CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Shan T, Liang X, Bi P, Zhang P, Liu W, Kuang S. Distinct populations of adipogenic and myogenic Myf5-lineage progenitors in white adipose tissues. J Lipid Res. 2013;54(8):2214–24. [PMID: 23740968 PMCID: 3708371].CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Walden TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am J Phys Endocrinol Metab. 2012;302(1):E19–31. [PMID: 21828341].CrossRefGoogle Scholar
  73. 73.
    Rosenwald M, Perdikari A, Rulicke T, Wolfrum C. Bi-directional interconversion of brite and white adipocytes. Nat Cell Biol. 2013;15(6):659–67. [PMID: 23624403].CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Min SY, Kady J, Nam M, Rojas-Rodriguez R, Berkenwald A, Kim JH, Noh HL, Kim JK, Cooper MP, Fitzgibbons T, Brehm MA, Corvera S. Human ‘brite/beige’ adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat Med. 2016;22(3):312–8. [PMID: 26808348 PMCID: 4777633].CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Accili D, Taylor SI. Targeted inactivation of the insulin receptor gene in mouse 3T3-L1 fibroblasts via homologous recombination. Proc Natl Acad Sci U S A. 1991;88(11):4708–12. [PMID: 2052553 PMCID: 51735].PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Tseng YH, Butte AJ, Kokkotou E, Yechoor VK, Taniguchi CM, Kriauciunas KM, Cypess AM, Niinobe M, Yoshikawa K, Patti ME, Kahn CR. Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nat Cell Biol. 2005;7(6):601–11. [PMID: 15895078].CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Divertie GD, Jensen MD, Miles JM. Stimulation of lipolysis in humans by physiological hypercortisolemia. Diabetes. 1991;40(10):1228–32. [PMID: 1936585].PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Xu C, He J, Jiang H, Zu L, Zhai W, Pu S, Xu G. Direct effect of glucocorticoids on lipolysis in adipocytes. Mol Endocrinol. 2009;23(8):1161–70. [PMID: 19443609].CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Smas CM, Chen L, Zhao L, Latasa MJ, Sul HS. Transcriptional repression of pref-1 by glucocorticoids promotes 3T3-L1 adipocyte differentiation. J Biol Chem. 1999;274(18):12632–41. [PMID: 10212243].PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Belanger C, Luu-The V, Dupont P, Tchernof A. Adipose tissue intracrinology: potential importance of local androgen/estrogen metabolism in the regulation of adiposity. Horm Metab Res = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2002;34(11–12):737–45. [PMID: 12660892].CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Pereira CD, Azevedo I, Monteiro R, Martins MJ. 11beta-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus. Diabetes Obes Metab. 2012;14(10):869–81. [PMID: 22321826].CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Bujalska IJ, Walker EA, Tomlinson JW, Hewison M, Stewart PM. 11Beta-hydroxysteroid dehydrogenase type 1 in differentiating omental human preadipocytes: from de-activation to generation of cortisol. Endocr Res. 2002;28(4):449–61. [PMID: 12530648].PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Stewart PM, Tomlinson JW. Cortisol, 11 beta-hydroxysteroid dehydrogenase type 1 and central obesity. Trends Endocrinol Metab. 2002;13(3):94–6. [PMID: 11893517].PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Meseguer A, Puche C, Cabero A. Sex steroid biosynthesis in white adipose tissue. Hormone Metab Res = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2002;34(11–12):731–6. [PMID: 12660891].CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Morreale de Escobar G, Obregon MJ, Escobar del Rey F. Role of thyroid hormone during early brain development. Eur J Endocrinol/Eur Fed Endocr Soc. 2004;151(Suppl 3):U25–37. [PMID: 15554884].CrossRefGoogle Scholar
  86. 86.
    Park EA, Song S, Olive M, Roesler WJ. CCAAT-enhancer-binding protein alpha (C/EBP alpha) is required for the thyroid hormone but not the retinoic acid induction of phosphoenolpyruvate carboxykinase (PEPCK) gene transcription. Biochem J. 1997;322(Pt 1):343–9. [PMID: 9078282 PMCID: 1218197].PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Carmona MC, Iglesias R, Obregon MJ, Darlington GJ, Villarroya F, Giralt M. Mitochondrial biogenesis and thyroid status maturation in brown fat require CCAAT/enhancer-binding protein alpha. J Biol Chem. 2002;277(24):21489–98. [PMID: 11940593].CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Nam SY, Lobie PE. The mechanism of effect of growth hormone on preadipocyte and adipocyte function. Obes Rev. 2000;1(2):73–86. [PMID: 12119989].PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Paniagua JA, Escandell-Morales JM, Gil-Contreras D, Berral de la Rosa FJ, Romero-Jimenez M, Gomez-Urbano A, Sanchez-Lopez A, Bellido E, Poyato A, Calatayud B, Vidal-Puig AJ. Central obesity and altered peripheral adipose tissue gene expression characterize the NAFLD patient with insulin resistance: role of nutrition and insulin challenge. Nutrition. 2014;30(2):177–85. [PMID: 24377452].CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature. 1998;395(6704):763–70. [PMID: 9796811].CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Friedman JM. Leptin, leptin receptors, and the control of body weight. Nutr Rev. 1998;56(2 Pt 2):s38–46; discussion s54–75 [PMID: 9564176].PubMedPubMedCentralGoogle Scholar
  92. 92.
    Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382(6588):250–2. [PMID: 8717038].CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest. 2003;111(9):1409–21. [PMID: 12727933 PMCID: 154448].CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341(12):879–84. [PMID: 10486419].CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351(10):987–97. [PMID: 15342807].CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest. 2002;109(10):1345–50. [PMID: 12021250 PMCID: 150981].CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346(8):570–8. [PMID: 11856796].CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature. 1998;394(6696):897–901. [PMID: 9732873].CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548–56. [PMID: 15181022].CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Unger RH, Zhou YT. Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes. 2001;50(Suppl 1):S118–21. [PMID: 11272168].PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Unger RH, Orci L. Diseases of liporegulation: new perspective on obesity and related disorders. FASEB J. 2001;15(2):312–21. [PMID: 11156947].CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004;145(5):2273–82. [PMID: 14726444].CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003;423(6941):762–9. [PMID: 12802337].CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A. 2001;98(4):2005–10. [PMID: 11172066 PMCID: 29372].CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112(1):91–100. [PMID: 12840063 PMCID: 162288].CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines: molecular links between obesity and atheroslcerosis. Am J Phys Heart Circ Phys. 2005;288(5):H2031–41. [PMID: 15653761].CrossRefGoogle Scholar
  107. 107.
    Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116(7):1784–92. [PMID: 16823476 PMCID: 1483172].CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes. 2001;50(5):1126–33. [PMID: 11334417].PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Mantzoros CS, Li T, Manson JE, Meigs JB, Hu FB. Circulating adiponectin levels are associated with better glycemic control, more favorable lipid profile, and reduced inflammation in women with type 2 diabetes. J Clin Endocrinol Metab. 2005;90(8):4542–8. [PMID: 15914524].CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297–307. [PMID: 17135584].CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Kanhai DA, Kranendonk ME, Uiterwaal CS, van der Graaf Y, Kappelle LJ, Visseren FL. Adiponectin and incident coronary heart disease and stroke. A systematic review and meta-analysis of prospective studies. Obes Rev. 2013;14(7):555–67. [PMID: 23495931].CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307–12. [PMID: 11201732].CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science. 2005;307(5708):426–30. [PMID: 15604363].CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H, Watanabe E, Takagi T, Akiyoshi M, Ohtsubo T, Kihara S, Yamashita S, Makishima M, Funahashi T, Yamanaka S, Hiramatsu R, Matsuzawa Y, Shimomura I. Retraction. Science. 2007;318(5850):565. [PMID: 17962537].CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Arner P. Visfatin–a true or false trail to type 2 diabetes mellitus. J Clin Endocrinol Metab. 2006;91(1):28–30. [PMID: 16401830].CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    de Souza Batista CM, Yang RZ, Lee MJ, Glynn NM, Yu DZ, Pray J, Ndubuizu K, Patil S, Schwartz A, Kligman M, Fried SK, Gong DW, Shuldiner AR, Pollin TI, McLenithan JC. Omentin plasma levels and gene expression are decreased in obesity. Diabetes. 2007;56(6):1655–61. [PMID: 17329619].CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Tan BK, Adya R, Farhatullah S, Lewandowski KC, O’Hare P, Lehnert H, Randeva HS. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome: ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes. 2008;57(4):801–8. [PMID: 18174521].CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Tan BK, Adya R, Farhatullah S, Chen J, Lehnert H, Randeva HS. Metformin treatment may increase omentin-1 levels in women with polycystic ovary syndrome. Diabetes. 2010;59(12):3023–31. [PMID: 20852028 PMCID: 2992762].CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Qi X, Li L, Yang G, Liu J, Li K, Tang Y, Liou H, Boden G. Circulating obestatin levels in normal subjects and in patients with impaired glucose regulation and type 2 diabetes mellitus. Clin Endocrinol. 2007;66(4):593–7. [PMID: 17371480].CrossRefGoogle Scholar
  120. 120.
    Catalan V, Gomez-Ambrosi J, Rotellar F, Silva C, Gil MJ, Rodriguez A, Cienfuegos JA, Salvador J, Fruhbeck G. The obestatin receptor (GPR39) is expressed in human adipose tissue and is down-regulated in obesity-associated type 2 diabetes mellitus. Clin Endocrinol. 2007;66(4):598–601. [PMID: 17371481].CrossRefGoogle Scholar
  121. 121.
    Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006;354(24):2552–63. [PMID: 16775236].CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Gavi S, Qurashi S, Melendez MM, Mynarcik DC, McNurlan MA, Gelato MC. Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes: response to Cho et al. Diabetes Care. 2007;30(3):e7.; author reply e8 [PMID: 17327302].CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Gavi S, Stuart LM, Kelly P, Melendez MM, Mynarcik DC, Gelato MC, McNurlan MA. Retinol-binding protein 4 is associated with insulin resistance and body fat distribution in nonobese subjects without type 2 diabetes. J Clin Endocrinol Metab. 2007;92(5):1886–90. [PMID: 17299074].CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975;72(9):3666–70. [PMID: 1103152 PMCID: 433057].PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984;312(5996):724–9. [PMID: 6392892].PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell. 2001;104(4):487–501. [PMID: 11239407].PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259(5091):87–91. [PMID: 7678183].PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Hotamisligil GS, Johnson RS, Distel RJ, Ellis R, Papaioannou VE, Spiegelman BM. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science. 1996;274(5291):1377–9. [PMID: 8910278].PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 1997;389(6651):610–4. [PMID: 9335502].CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Hofmann C, Lorenz K, Braithwaite SS, Colca JR, Palazuk BJ, Hotamisligil GS, Spiegelman BM. Altered gene expression for tumor necrosis factor-alpha and its receptors during drug and dietary modulation of insulin resistance. Endocrinology. 1994;134(1):264–70. [PMID: 8275942].CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Xing H, Northrop JP, Grove JR, Kilpatrick KE, Su JL, Ringold GM. TNF alpha-mediated inhibition and reversal of adipocyte differentiation is accompanied by suppressed expression of PPARgamma without effects on Pref-1 expression. Endocrinology. 1997;138(7):2776–83. [PMID: 9202217].PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Ruan H, Hacohen N, Golub TR, Van Parijs L, Lodish HF. Tumor necrosis factor-alpha suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3-L1 adipocytes: nuclear factor-kappaB activation by TNF-alpha is obligatory. Diabetes. 2002;51(5):1319–36. [PMID: 11978627].PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006;116(11):3015–25. [PMID: 17053832 PMCID: 1616196].CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Bastard JP, Jardel C, Delattre J, Hainque B, Bruckert E, Oberlin F. Evidence for a link between adipose tissue interleukin-6 content and serum C-reactive protein concentrations in obese subjects. Circulation. 1999;99(16):2221–2. [PMID: 10217702].PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Fernandez-Real JM, Ricart W. Insulin resistance and chronic cardiovascular inflammatory syndrome. Endocr Rev. 2003;24(3):278–301. [PMID: 12788800].PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Wang B, Jenkins JR, Trayhurn P. Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: integrated response to TNF-alpha. Am J Phys Endocrinol Metab. 2005;288(4):E731–40. [PMID: 15562246].CrossRefGoogle Scholar
  137. 137.
    Chavey C, Lazennec G, Lagarrigue S, Clape C, Iankova I, Teyssier J, Annicotte JS, Schmidt J, Mataki C, Yamamoto H, Sanches R, Guma A, Stich V, Vitkova M, Jardin-Watelet B, Renard E, Strieter R, Tuthill A, Hotamisligil GS, Vidal-Puig A, Zorzano A, Langin D, Fajas L. CXC ligand 5 is an adipose-tissue derived factor that links obesity to insulin resistance. Cell Metab. 2009;9(4):339–49. [PMID: 19356715 PMCID: 2804846].CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Duplus E, Glorian M, Forest C. Fatty acid regulation of gene transcription. J Biol Chem. 2000;275(40):30749–52. [PMID: 10934217].CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Food and Agriculture Organization of the United Nations. Fats and fatty acids in human nutrition: report of an expert consultation: 10–14 November 2008, Geneva. Rome: Food and Agriculture Organization of the United Nations; 2010.Google Scholar
  140. 140.
    Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011;58(20):2047–67. [PMID: 22051327].CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Gonzales AM, Orlando RA. Role of adipocyte-derived lipoprotein lipase in adipocyte hypertrophy. Nutr Metab. 2007;4:22. [PMID: 17971230 PMCID: 2174487].CrossRefGoogle Scholar
  142. 142.
    Storch J, Thumser AE. The fatty acid transport function of fatty acid-binding proteins. Biochim Biophys Acta. 2000;1486(1):28–44. [PMID: 10856711].PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Jakobsson A, Westerberg R, Jacobsson A. Fatty acid elongases in mammals: their regulation and roles in metabolism. Prog Lipid Res. 2006;45(3):237–49. [PMID: 16564093].CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Coleman RA, Lee DP. Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res. 2004;43(2):134–76. [PMID: 14654091].PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Yu YH, Zhang Y, Oelkers P, Sturley SL, Rader DJ, Ginsberg HN. Posttranscriptional control of the expression and function of diacylglycerol acyltransferase-1 in mouse adipocytes. J Biol Chem. 2002;277(52):50876–84. [PMID: 12407108].CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, Smith RJ, Smith SR, Endocrine S, American Diabetes A. European Association for the Study of D. Obesity and type 2 diabetes: what can be unified and what needs to be individualized? Diabetes Care. 2011;34(6):1424–30. [PMID: 21602431 PMCID: 3114323].CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Sullivan PW, Morrato EH, Ghushchyan V, Wyatt HR, Hill JO. Obesity, inactivity, and the prevalence of diabetes and diabetes-related cardiovascular comorbidities in the U.S., 2000–2002. Diabetes Care. 2005;28(7):1599–603. [PMID: 15983307].PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333–46. [PMID: 15823385].CrossRefPubMedGoogle Scholar
  149. 149.
    Kahn CR. Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes. 1994;43(8):1066–84. [PMID: 8039601].PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Beck-Nielsen H, Groop LC. Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest. 1994;94(5):1714–21. [PMID: 7962519 PMCID: 294561].CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Bjorntorp P. Metabolic implications of body fat distribution. Diabetes Care. 1991;14(12):1132–43. [PMID: 1773700].PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Frontini A, Cinti S. Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 2010;11(4):253–6. [PMID: 20374956].CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Rich-Edwards JW, Colditz GA, Stampfer MJ, Willett WC, Gillman MW, Hennekens CH, Speizer FE, Manson JE. Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med. 1999;130(4 Pt 1):278–84. [PMID: 10068385].PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Whincup PH, Kaye SJ, Owen CG, Huxley R, Cook DG, Anazawa S, Barrett-Connor E, Bhargava SK, Birgisdottir BE, Carlsson S, de Rooij SR, Dyck RF, Eriksson JG, Falkner B, Fall C, Forsen T, Grill V, Gudnason V, Hulman S, Hypponen E, Jeffreys M, Lawlor DA, Leon DA, Minami J, Mishra G, Osmond C, Power C, Rich-Edwards JW, Roseboom TJ, Sachdev HS, Syddall H, Thorsdottir I, Vanhala M, Wadsworth M, Yarbrough DE. Birth weight and risk of type 2 diabetes: a systematic review. JAMA. 2008;300(24):2886–97. [PMID: 19109117].CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Dyck RF, Klomp H, Tan L. From “thrifty genotype” to “hefty fetal phenotype”: the relationship between high birthweight and diabetes in Saskatchewan Registered Indians. Can J Public Health = Revue canadienne de sante publique. 2001;92(5):340–4. [PMID: 11702485].PubMedPubMedCentralGoogle Scholar
  156. 156.
    Harder T, Rodekamp E, Schellong K, Dudenhausen JW, Plagemann A. Birth weight and subsequent risk of type 2 diabetes: a meta-analysis. Am J Epidemiol. 2007;165(8):849–57. [PMID: 17215379].CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Coleman R, Bell RM. Triacylglycerol synthesis in isolated fat cells. Studies on the microsomal diacylglycerol acyltransferase activity using ethanol-dispersed diacylglycerols. J Biol Chem. 1976;251(15):4537–43. [PMID: 947894].PubMedPubMedCentralGoogle Scholar
  158. 158.
    Greenberg AS, Egan JJ, Wek SA, Garty NB, Blanchette-Mackie EJ, Londos C. Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets. J Biol Chem. 1991;266(17):11341–6. [PMID: 2040638].PubMedPubMedCentralGoogle Scholar
  159. 159.
    Bajaj M, Pratipanawatr T, Berria R, Pratipanawatr W, Kashyap S, Cusi K, Mandarino L, DeFronzo RA. Free fatty acids reduce splanchnic and peripheral glucose uptake in patients with type 2 diabetes. Diabetes. 2002;51(10):3043–8. [PMID: 12351445].PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, Bajaj M, Mandarino L, DeFronzo R, Cusi K. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes. 2003;52(10):2461–74. [PMID: 14514628].PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M, Bergamini E, Mosca F, Di Mario U, Del Prato S, Marchetti P. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes. 2002;51(5):1437–42. [PMID: 11978640].PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Rodriguez-Cuenca S, Carobbio S, Velagapudi VR, Barbarroja N, Moreno-Navarrete JM, Tinahones FJ, Fernandez-Real JM, Oresic M, Vidal-Puig A. Peroxisome proliferator-activated receptor gamma-dependent regulation of lipolytic nodes and metabolic flexibility. Mol Cell Biol. 2012;32(8):1555–65. [PMID: 22310664 PMCID: 3318581]. MCB.06154–11 [pii]].CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Martin SS, Qasim A, Reilly MP. Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol. 2008;52(15):1201–10. [PMID: 18926322 PMCID: 4556270].CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF. Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Diabetes. 1996;45(5):699–701. [PMID: 8621027].PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Asterholm IW, Scherer PE. Enhanced metabolic flexibility associated with elevated adiponectin levels. Am J Pathol. 2010;176(3):1364–76. [PMID: 20093494 PMCID: 2832156S0002-9440(10)60448-8 [pii]].CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001;50(8):1844–50. [PMID: 11473047].PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104(6):787–94. [PMID: 10491414 PMCID: 408438].CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–39. [PMID: 17928588].CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63(2):492–8. [PMID: 3522621].CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Sandoval DA, D’Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev. 2015;95(2):513–48. [PMID: 25834231].CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13(1):11–26. [PMID: 27941935].CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med. 2002;8(12):1376–82. [PMID: 12426561].CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosci. 2002;5(6):566–72. [PMID: 12021765].CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003;112(12):1821–30. [PMID: 14679177 PMCID: 296998].CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, Busse R, Bouloumie A. From blood monocytes to adipose tissue-resident macrophages: induction of diapedesis by human mature adipocytes. Diabetes. 2004;53(5):1285–92. [PMID: 15111498].PubMedCrossRefPubMedCentralGoogle Scholar
  176. 176.
    Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115(5):1111–9. [PMID: 15864338 PMCID: 1087185].CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, Tsuneyama K, Nagai Y, Takatsu K, Urakaze M, Kobayashi M, Tobe K. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes. 2009;58(11):2574–82. [PMID: 19690061 PMCID: 2768159].CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117(1):175–84. [PMID: 17200717 PMCID: 1716210].CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18(3):363–74. [PMID: 22395709].CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95(5):2409–15. [PMID: 7738205 PMCID: 295872.CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009;15(8):930–9. [PMID: 19633656 PMCID: 3115752.CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Harford KA, Reynolds CM, McGillicuddy FC, Roche HM. Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue. Proc Nutr Soc. 2011;70(4):408–17. [PMID: 21835098].CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science. 2011;332(6026):243–7. [PMID: 21436399 PMCID: 3144160].CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J, Lin M, Brenner MB, Olefsky JM. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med. 2012;18(9):1407–12. [PMID: 22863787 PMCID: 3491143].CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Peraldi P, Hotamisligil GS, Buurman WA, White MF, Spiegelman BM. Tumor necrosis factor (TNF)-alpha inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J Biol Chem. 1996;271(22):13018–22. [PMID: 8662983].PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science. 2001;293(5535):1673–7. [PMID: 11533494].CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem. 2008;283(51):35375–82. [PMID: 18952604 PMCID: 2602883].CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Ye J. Regulation of PPARgamma function by TNF-alpha. Biochem Biophys Res Commun. 2008;374(3):405–8.]. [PMID: 18655773 PMCID: 2596979].CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011;12(5):408–15. [PMID: 21478880 PMCID: 4090391].CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Mills KH, Dunne A. Immune modulation: IL-1, master mediator or initiator of inflammation. Nat Med. 2009;15(12):1363–4. [PMID: 19966773].CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Netea MG, Nold-Petry CA, Nold MF, Joosten LA, Opitz B, van der Meer JH, van de Veerdonk FL, Ferwerda G, Heinhuis B, Devesa I, Funk CJ, Mason RJ, Kullberg BJ, Rubartelli A, van der Meer JW, Dinarello CA. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood. 2009;113(10):2324–35. [PMID: 19104081 PMCID: 2652374].CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011;17(2):179–88. [PMID: 21217695 PMCID: 3076025].CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796–808. [PMID: 14679176 PMCID: 296995].CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol. 2008;103(6):1372–9. [PMID: 18510618].CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obes Res. 2001;9(7):414–7. [PMID: 11445664].CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Ruge T, Lockton JA, Renstrom F, Lystig T, Sukonina V, Svensson MK, Eriksson JW. Acute hyperinsulinemia raises plasma interleukin-6 in both nondiabetic and type 2 diabetes mellitus subjects, and this effect is inversely associated with body mass index. Metab Clin Exp. 2009;58(6):860–6. [PMID: 19375766].CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest S, Muller YD, Hansen AM, Reinecke M, Konrad D, Gassmann M, Reimann F, Halban PA, Gromada J, Drucker DJ, Gribble FM, Ehses JA, Donath MY. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med. 2011;17(11):1481–9. [PMID: 22037645 PMCID: 4286294].CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8(8):457–65. [PMID: 22473333].CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    Pedersen BK. A muscular twist on the fate of fat. N Engl J Med. 2012;366(16):1544–5. [PMID: 22512488].CrossRefPubMedPubMedCentralGoogle Scholar
  200. 200.
    van Exel E, Gussekloo J, de Craen AJ, Frolich M, Bootsma-Van Der Wiel A, Westendorp RG, Leiden 85 Plus S. Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes: the Leiden 85-Plus Study. Diabetes. 2002;51(4):1088–92. [PMID: 11916930].PubMedCrossRefPubMedCentralGoogle Scholar
  201. 201.
    Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K. Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes. 2005;54(8):2277–86. [PMID: 16046292].PubMedCrossRefPubMedCentralGoogle Scholar
  202. 202.
    Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307(5708):384–7. [PMID: 15662004].CrossRefPubMedPubMedCentralGoogle Scholar
  203. 203.
    Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci U S A. 2003;100(13):7996–8001. [PMID: 12808136 PMCID: 164701].CrossRefPubMedPubMedCentralGoogle Scholar
  204. 204.
    Asmann YW, Stump CS, Short KR, Coenen-Schimke JM, Guo Z, Bigelow ML, Nair KS. Skeletal muscle mitochondrial functions, mitochondrial DNA copy numbers, and gene transcript profiles in type 2 diabetic and nondiabetic subjects at equal levels of low or high insulin and euglycemia. Diabetes. 2006;55(12):3309–19. [PMID: 17130474].CrossRefPubMedPubMedCentralGoogle Scholar
  205. 205.
    Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes. 2002;51(10):2944–50. [PMID: 12351431].PubMedCrossRefPubMedCentralGoogle Scholar
  206. 206.
    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(6 Pt 1):E1130–41. [PMID: 10600804].PubMedPubMedCentralGoogle Scholar
  207. 207.
    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(14):2051–60. [PMID: 10544188].PubMedCrossRefPubMedCentralGoogle Scholar
  208. 208.
    Szendroedi J, Phielix E, Roden M. The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol. 2011;8(2):92–103. [PMID: 21912398].CrossRefPubMedPubMedCentralGoogle Scholar
  209. 209.
    Hwang H, Bowen BP, Lefort N, Flynn CR, De Filippis EA, Roberts C, Smoke CC, Meyer C, Hojlund K, Yi Z, Mandarino LJ. Proteomics analysis of human skeletal muscle reveals novel abnormalities in obesity and type 2 diabetes. Diabetes. 2010;59(1):33–42. [PMID: 19833877 PMCID: 2797941].CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Turner N, Heilbronn LK. Is mitochondrial dysfunction a cause of insulin resistance? Trends Endocrinol Metab. 2008;19(9):324–30. [PMID: 18804383].CrossRefPubMedPubMedCentralGoogle Scholar
  211. 211.
    Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney GJ. Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes. 2007;56(8):2085–92. [PMID: 17519422].CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Hancock CR, Han DH, Chen M, Terada S, Yasuda T, Wright DC, Holloszy JO. High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci U S A. 2008;105(22):7815–20. [PMID: 18509063 PMCID: 2409421].CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Turner N, Hariharan K, TidAng J, Frangioudakis G, Beale SM, Wright LE, Zeng XY, Leslie SJ, Li JY, Kraegen EW, Cooney GJ, Ye JM. Enhancement of muscle mitochondrial oxidative capacity and alterations in insulin action are lipid species dependent: potent tissue-specific effects of medium-chain fatty acids. Diabetes. 2009;58(11):2547–54. [PMID: 19720794 PMCID: 2768163].CrossRefPubMedPubMedCentralGoogle Scholar
  214. 214.
    Pagel-Langenickel I, Bao J, Pang L, Sack MN. The role of mitochondria in the pathophysiology of skeletal muscle insulin resistance. Endocr Rev. 2010;31(1):25–51 [. [PMID: 19861693 PMCID: 2852205].].CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Muoio DM. Intramuscular triacylglycerol and insulin resistance: guilty as charged or wrongly accused? Biochim Biophys Acta. 2010;1801(3):281–8. [PMID: 19958841 PMCID: 4428562].CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Brunmair B, Staniek K, Gras F, Scharf N, Althaym A, Clara R, Roden M, Gnaiger E, Nohl H, Waldhausl W, Furnsinn C. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes. 2004;53(4):1052–9. [PMID: 15047621].PubMedCrossRefPubMedCentralGoogle Scholar
  217. 217.
    Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996;97(12):2859–65. [PMID: 8675698 PMCID: 507380].CrossRefPubMedPubMedCentralGoogle Scholar
  218. 218.
    Samocha-Bonet D, Campbell LV, Mori TA, Croft KD, Greenfield JR, Turner N, Heilbronn LK. Overfeeding reduces insulin sensitivity and increases oxidative stress, without altering markers of mitochondrial content and function in humans. PLoS One. 2012;7(5):e36320. [PMID: 22586466 PMCID: 3346759].CrossRefPubMedPubMedCentralGoogle Scholar
  219. 219.
    Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Dela F. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia. 2007;50(4):790–6. [PMID: 17334651 PMCID: 1820754].CrossRefPubMedPubMedCentralGoogle Scholar
  220. 220.
    Paolisso G, Gambardella A, Tagliamonte MR, Saccomanno F, Salvatore T, Gualdiero P, D’Onofrio MV, Howard BV. Does free fatty acid infusion impair insulin action also through an increase in oxidative stress? J Clin Endocrinol Metab. 1996;81(12):4244–8. [PMID: 8954022].CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    De Mattia G, Bravi MC, Laurenti O, Cassone-Faldetta M, Armiento A, Ferri C, Balsano F. Influence of reduced glutathione infusion on glucose metabolism in patients with non-insulin-dependent diabetes mellitus. Metab Clin Exp. 1998;47(8):993–7. [PMID: 9711998].PubMedCrossRefPubMedCentralGoogle Scholar
  222. 222.
    Mielgo-Ayuso J, Barrenechea L, Alcorta P, Larrarte E, Margareto J, Labayen I. Effects of dietary supplementation with epigallocatechin-3-gallate on weight loss, energy homeostasis, cardiometabolic risk factors and liver function in obese women: randomised, double-blind, placebo-controlled clinical trial. Br J Nutr. 2014;111(7):1263–71. [PMID: 24299662].CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    Czernichow S, Vergnaud AC, Galan P, Arnaud J, Favier A, Faure H, Huxley R, Hercberg S, Ahluwalia N. Effects of long-term antioxidant supplementation and association of serum antioxidant concentrations with risk of metabolic syndrome in adults. Am J Clin Nutr. 2009;90(2):329–35. [PMID: 19491388].CrossRefPubMedPubMedCentralGoogle Scholar
  224. 224.
    Schroder M, Kaufman RJ. ER stress and the unfolded protein response. Mutat Res. 2005;569(1–2):29–63. [PMID: 15603751].CrossRefPubMedPubMedCentralGoogle Scholar
  225. 225.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 2004;306(5695):457–61. [PMID: 15486293].CrossRefPubMedPubMedCentralGoogle Scholar
  226. 226.
    de Luca C, Olefsky JM. Stressed out about obesity and insulin resistance. Nat Med. 2006;12(1):41–2.; discussion 42 [PMID: 16397561].CrossRefPubMedPubMedCentralGoogle Scholar
  227. 227.
    Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers MG Jr, Ozcan U. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009;9(1):35–51. [PMID: 19117545].CrossRefPubMedPubMedCentralGoogle Scholar
  228. 228.
    Kars M, Yang L, Gregor MF, Mohammed BS, Pietka TA, Finck BN, Patterson BW, Horton JD, Mittendorfer B, Hotamisligil GS, Klein S. Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes. 2010;59(8):1899–905. [PMID: 20522594 PMCID: 2911053].CrossRefPubMedPubMedCentralGoogle Scholar
  229. 229.
    Muoio DM, Dohm GL, Fiedorek FT Jr, Tapscott EB, Coleman RA. Leptin directly alters lipid partitioning in skeletal muscle. Diabetes. 1997;46(8):1360–3. [PMID: 9231663].PubMedCrossRefPubMedCentralGoogle Scholar
  230. 230.
    Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–51. [PMID: 15864352 PMCID: 1087172.CrossRefPubMedPubMedCentralGoogle Scholar
  231. 231.
    Paniagua JA. Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome. World J Diabetes. 2016;7(19):483–514. [PMID: 27895819 PMCID: 5107710].CrossRefPubMedPubMedCentralGoogle Scholar
  232. 232.
    Utzschneider KM, Kahn SE. Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab. 2006;91(12):4753–61. [PMID: 16968800].CrossRefPubMedPubMedCentralGoogle Scholar
  233. 233.
    Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, Tio F, Hardies J, Darland C, Musi N, Webb A, Portillo-Sanchez P. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165(5):305–15. [PMID: 27322798].CrossRefPubMedPubMedCentralGoogle Scholar
  234. 234.
    Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003;38(2):413–9. [PMID: 12883485].CrossRefPubMedPubMedCentralGoogle Scholar
  235. 235.
    Steil GM, Trivedi N, Jonas JC, Hasenkamp WM, Sharma A, Bonner-Weir S, Weir GC. Adaptation of beta-cell mass to substrate oversupply: enhanced function with normal gene expression. Am J Phys Endocrinol Metab. 2001;280(5):E788–96. [PMID: 11287362].CrossRefGoogle Scholar
  236. 236.
    Chen C, Hosokawa H, Bumbalo LM, Leahy JL. Mechanism of compensatory hyperinsulinemia in normoglycemic insulin-resistant spontaneously hypertensive rats. Augmented enzymatic activity of glucokinase in beta-cells. J Clin Invest. 1994;94(1):399–404. [PMID: 8040280 PMCID: 296322].CrossRefPubMedPubMedCentralGoogle Scholar
  237. 237.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–10. [PMID: 12502499].PubMedCrossRefPubMedCentralGoogle Scholar
  238. 238.
    Prentki M. New insights into pancreatic beta-cell metabolic signaling in insulin secretion. Eur J Endocrinol/Eur Fed Endocr Soc. 1996;134(3):272–86. [PMID: 8616523].CrossRefGoogle Scholar
  239. 239.
    Lebrun P, Montminy MR, Van Obberghen E. Regulation of the pancreatic duodenal homeobox-1 protein by DNA-dependent protein kinase. J Biol Chem. 2005;280(46):38203–10. [PMID: 16166097].CrossRefPubMedPubMedCentralGoogle Scholar
  240. 240.
    Roduit R, Nolan C, Alarcon C, Moore P, Barbeau A, Delghingaro-Augusto V, Przybykowski E, Morin J, Masse F, Massie B, Ruderman N, Rhodes C, Poitout V, Prentki M. A role for the malonyl-CoA/long-chain acyl-CoA pathway of lipid signaling in the regulation of insulin secretion in response to both fuel and nonfuel stimuli. Diabetes. 2004;53(4):1007–19. [PMID: 15047616].PubMedCrossRefPubMedCentralGoogle Scholar
  241. 241.
    Prentki M, Joly E, El-Assaad W, Roduit R. Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes. 2002;51(Suppl 3):S405–13. [PMID: 12475783].PubMedCrossRefPubMedCentralGoogle Scholar
  242. 242.
    Paniagua JA, de la Sacristana AG, Sanchez E, Romero I, Vidal-Puig A, Berral FJ, Escribano A, Moyano MJ, Perez-Martinez P, Lopez-Miranda J, Perez-Jimenez F. A MUFA-rich diet improves posprandial glucose, lipid and GLP-1 responses in insulin-resistant subjects. J Am Coll Nutr. 2007;26(5):434–44. [PMID: 17914131].PubMedCrossRefPubMedCentralGoogle Scholar
  243. 243.
    Nolan CJ, Leahy JL, Delghingaro-Augusto V, Moibi J, Soni K, Peyot ML, Fortier M, Guay C, Lamontagne J, Barbeau A, Przybytkowski E, Joly E, Masiello P, Wang S, Mitchell GA, Prentki M. Beta cell compensation for insulin resistance in Zucker fatty rats: increased lipolysis and fatty acid signalling. Diabetologia. 2006;49(9):2120–30. [PMID: 16868750].CrossRefPubMedPubMedCentralGoogle Scholar
  244. 244.
    Yusta B, Baggio LL, Estall JL, Koehler JA, Holland DP, Li H, Pipeleers D, Ling Z, Drucker DJ. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006;4(5):391–406. [PMID: 17084712].CrossRefPubMedPubMedCentralGoogle Scholar
  245. 245.
    Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):153–65. [PMID: 16517403].CrossRefPubMedPubMedCentralGoogle Scholar
  246. 246.
    Muscelli E, Mari A, Casolaro A, Camastra S, Seghieri G, Gastaldelli A, Holst JJ, Ferrannini E. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes. 2008;57(5):1340–8. [PMID: 18162504].CrossRefPubMedPubMedCentralGoogle Scholar
  247. 247.
    Ahren B. Autonomic regulation of islet hormone secretion--implications for health and disease. Diabetologia. 2000;43(4):393–410. [PMID: 10819232].CrossRefPubMedPubMedCentralGoogle Scholar
  248. 248.
    Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, Song KH, Yoo SJ, Kang MI, Cha BY, Lee KW, Son HY, Kang SK, Kim HS, Lee IK, Bonner-Weir S. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab. 2003;88(5):2300–8. [PMID: 12727989].CrossRefPubMedPubMedCentralGoogle Scholar
  249. 249.
    Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem. 2004;279(41):42351–4. [PMID: 15258147].CrossRefPubMedPubMedCentralGoogle Scholar
  250. 250.
    Donath MY, Ehses JA, Maedler K, Schumann DM, Ellingsgaard H, Eppler E, Reinecke M. Mechanisms of beta-cell death in type 2 diabetes. Diabetes. 2005;54(Suppl 2):S108–13. [PMID: 16306327].PubMedCrossRefPubMedCentralGoogle Scholar
  251. 251.
    Brownlee M. A radical explanation for glucose-induced beta cell dysfunction. J Clin Invest. 2003;112(12):1788–90. [PMID: 14679173 PMCID: 297003].CrossRefPubMedPubMedCentralGoogle Scholar
  252. 252.
    Krauss S, Zhang CY, Scorrano L, Dalgaard LT, St-Pierre J, Grey ST, Lowell BB. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest. 2003;112(12):1831–42. [PMID: 14679178 PMCID: 297000].CrossRefPubMedPubMedCentralGoogle Scholar
  253. 253.
    Oyadomari S, Araki E, Mori M. Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis. 2002;7(4):335–45. [PMID: 12101393].PubMedCrossRefPubMedCentralGoogle Scholar
  254. 254.
    Puri S, Folias AE, Hebrok M. Plasticity and dedifferentiation within the pancreas: development, homeostasis, and disease. Cell Stem Cell. 2015;16(1):18–31. [PMID: 25465113 PMCID: 4289422].CrossRefPubMedPubMedCentralGoogle Scholar
  255. 255.
    Hosoya M, Kunisada Y, Kurisaki A, Asashima M. Induction of differentiation of undifferentiated cells into pancreatic beta cells in vertebrates. Int J Dev Biol. 2012;56(5):313–23. [PMID: 22689376].CrossRefPubMedPubMedCentralGoogle Scholar
  256. 256.
    Kim JB, Sarraf P, Wright M, Yao KM, Mueller E, Solanes G, Lowell BB, Spiegelman BM. Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. J Clin Invest. 1998;101(1):1–9. [PMID: 9421459 PMCID: 508533].CrossRefPubMedPubMedCentralGoogle Scholar
  257. 257.
    Kim JB, Wright HM, Wright M, Spiegelman BM. ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand. Proc Natl Acad Sci U S A. 1998;95(8):4333–7. [PMID: 9539737 PMCID: 22489].PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Spiegelman BM, Frank M, Green H. Molecular cloning of mRNA from 3T3 adipocytes. Regulation of mRNA content for glycerophosphate dehydrogenase and other differentiation-dependent proteins during adipocyte development. J Biol Chem. 1983;258(16):10083–9. [PMID: 6411703].PubMedPubMedCentralGoogle Scholar
  259. 259.
    Mandrup S, Lane MD. Regulating adipogenesis. J Biol Chem. 1997;272(9):5367–70. [PMID: 9102400].PubMedCrossRefPubMedCentralGoogle Scholar
  260. 260.
    Sung HK, Doh KO, Son JE, Park JG, Bae Y, Choi S, Nelson SM, Cowling R, Nagy K, Michael IP, Koh GY, Adamson SL, Pawson T, Nagy A. Adipose vascular endothelial growth factor regulates metabolic homeostasis through angiogenesis. Cell Metab. 2013;17(1):61–72. [PMID: 23312284]. S1550-4131(12)00501-3 [pii]].CrossRefPubMedPubMedCentralGoogle Scholar
  261. 261.
    Maroto M, Bone RA, Dale JK. Somitogenesis. Development. 2012;139(14):2453–6. [PMID: 22736241].CrossRefPubMedPubMedCentralGoogle Scholar
  262. 262.
    Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454(7207):961–7. [PMID: 18719582 PMCID: 2583329].CrossRefPubMedPubMedCentralGoogle Scholar
  263. 263.
    Kajimura S, Seale P, Tomaru T, Erdjument-Bromage H, Cooper MP, Ruas JL, Chin S, Tempst P, Lazar MA, Spiegelman BM. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 2008;22(10):1397–409. [PMID: 18483224 PMCID: 2377193].CrossRefPubMedPubMedCentralGoogle Scholar
  264. 264.
    Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature. 2008;454(7207):1000–4. [PMID: 18719589 PMCID: 2745972].CrossRefPubMedPubMedCentralGoogle Scholar
  265. 265.
    Bullo M, Garcia-Lorda P, Megias I, Salas-Salvado J. Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obes Res. 2003;11(4):525–31. [PMID: 12690081].CrossRefPubMedPubMedCentralGoogle Scholar
  266. 266.
    Prieur X, Mok CY, Velagapudi VR, Nunez V, Fuentes L, Montaner D, Ishikawa K, Camacho A, Barbarroja N, O’Rahilly S, Sethi JK, Dopazo J, Oresic M, Ricote M, Vidal-Puig A. Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes. 2011;60(3):797–809. [PMID: 21266330 PMCID: 3046840].CrossRefPubMedPubMedCentralGoogle Scholar
  267. 267.
    Rosen BS, Cook KS, Yaglom J, Groves DL, Volanakis JE, Damm D, White T, Spiegelman BM. Adipsin and complement factor D activity: an immune-related defect in obesity. Science. 1989;244(4911):1483–7. [PMID: 2734615].PubMedCrossRefPubMedCentralGoogle Scholar
  268. 268.
    Kasbi Chadli F, Andre A, Prieur X, Loirand G, Meynier A, Krempf M, Nguyen P, Ouguerram K. n-3 PUFA prevent metabolic disturbances associated with obesity and improve endothelial function in golden Syrian hamsters fed with a high-fat diet. Br J Nutr. 2012;107(9):1305–15. [PMID: 21920060].CrossRefPubMedPubMedCentralGoogle Scholar
  269. 269.
    Guilherme A, Virbasius JV, Puri V, Czech MP. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol. 2008;9(5):367–77. [PMID: 18401346 PMCID: 2886982].CrossRefPubMedPubMedCentralGoogle Scholar
  270. 270.
    Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121(6):2094–101. [PMID: 21633177 PMCID: 3104761].CrossRefPubMedPubMedCentralGoogle Scholar
  271. 271.
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–9. [PMID: 3899825].PubMedCrossRefPubMedCentralGoogle Scholar
  272. 272.
    Hotamisligil GS. Inflammation, TNF alpha and insulin resistance. Philadelphia: Lippincott-Raven Publishers; 2003.Google Scholar
  273. 273.
    Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature. 2002;420(6913):333–6. [PMID: 12447443].CrossRefPubMedPubMedCentralGoogle Scholar
  274. 274.
    Despres JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, Rodes-Cabau J, Bertrand OF, Poirier P. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol. 2008;28(6):1039–49. [PMID: 18356555].CrossRefPubMedPubMedCentralGoogle Scholar
  275. 275.
    Kim JY, van de Wall E, Laplante M, Azzara A, Trujillo ME, Hofmann SM, Schraw T, Durand JL, Li H, Li G, Jelicks LA, Mehler MF, Hui DY, Deshaies Y, Shulman GI, Schwartz GJ, Scherer PE. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J Clin Invest. 2007;117(9):2621–37. [PMID: 17717599 PMCID: 1950456].CrossRefPubMedPubMedCentralGoogle Scholar
  276. 276.
    Meier JJ, Bonadonna RC. Role of reduced beta-cell mass versus impaired beta-cell function in the pathogenesis of type 2 diabetes. Diabetes Care. 2013;36(Suppl 2):S113–9. [PMID: 23882035 PMCID: 3920783].CrossRefPubMedPubMedCentralGoogle Scholar
  277. 277.
    Garber AJ. Incretin effects on beta-cell function, replication, and mass: the human perspective. Diabetes Care. 2011;34(Suppl 2):S258–63. [PMID: 21525465 PMCID: 3632189].CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Juan Antonio Paniagua González
    • 1
    • 2
  • Antonio Vidal-Puig
    • 3
    • 4
  1. 1.Insulin Resistance, Metabolism and Adipose Tissue Unit, Maimonides Institute of Biomedical ResearchUniversity Hospital Reina SofiaCórdobaSpain
  2. 2.Endocrinology and Nutrition ServicesUniversity Hospital Reina SofiaCordobaSpain
  3. 3.Wellcome Trust MRC Institute Metabolic Science, MRC MDUUniversity of CambridgeCambridgeUK
  4. 4.Wellcome Trust Sanger InstituteHinxtonUK

Personalised recommendations