• 1
    Danaei G, Ding EL, Mozaffarian D, Taylor B, Rehm J, Murray CJ & Ezzati M (2009) The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS Med 6, e1000058, doi: DOI: 10.1371/journal.pmed.1000058.
  • 2
    Misra A & Khurana L (2008) Obesity and the metabolic syndrome in developing countries. J Clin Endocrinol Metab 93, S9S30.
  • 3
    Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC & O’Rahilly S (1997) Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16, 303306.
  • 4
    Krude H, Biebermann H, Luck W, Horn R, Brabant G & Gruters A (1998) Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19, 155157.
  • 5
    Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA et al. (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903908.
  • 6
    Vaisse C, Clement K, Guy-Grand B & Froguel P (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20, 113114.
  • 7
    Bell CG, Walley AJ & Froguel P (2005) The genetics of human obesity. Nat Rev Genet 6, 221234.
  • 8
    Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, Perusse L & Bouchard C (2006) The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14, 529644.
  • 9
    Walley AJ, Asher JE & Froguel P (2009) The genetic contribution to non-syndromic human obesity. Nat Rev Genet 10, 431442.
  • 10
    Chandra RK (1981) Immune response in overnutrition. Cancer Res 41, 37953796.
  • 11
    Ebstein W (1876) Zur therapie des Diabetes mellitus, insbesondere uber die Anwendung des salicylsauren Natron bei demselben. Berliner Klinische Wochenschrift 13, 337340.
  • 12
    Reid EW (1901) Transport of fluid by certain epithelia. J Physiol 26, 436444.
  • 13
    Shoelson S (2002) Invited comment on W. Ebstein: on the therapy of diabetes mellitus, in particular on the application of sodium salicylate. J Mol Med 80, 618619.
  • 14
    Nieman DC, Nehlsen-Cannarella SI, Henson DA, Butterworth DE, Fagoaga OR, Warren BJ & Rainwater MK (1996) Immune response to obesity and moderate weight loss. Int J Obes Relat Metab Disord 20, 353360.
  • 15
    Womack J, Tien PC, Feldman J, Shin JH, Fennie K, Anastos K, Cohen MH, Bacon MC & Minkoff H (2007) Obesity and immune cell counts in women. Metabolism 56, 9981004.
  • 16
    Shoelson SE, Lee J & Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116, 17931801.
  • 17
    Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M & Shoelson SE (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293, 16731677.
  • 18
    Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444, 860867.
  • 19
    Wellen KE & Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115, 11111119.
  • 20
    Purnell JQ, Kahn SE, Samuels MH, Brandon D, Loriaux DL & Brunzell JD (2009) Enhanced cortisol production rates, free cortisol, and 11beta-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss. Am J Physiol Endocrinol Metab 296, E351E357.
  • 21
    Seckl JR & Walker BR (2001) Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action. Endocrinology 142, 13711376.
  • 22
    Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CR, Seckl JR et al. (1997) 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci USA 94, 1492414929.
  • 23
    Morton NM, Holmes MC, Fievet C, Staels B, Tailleux A, Mullins JJ & Seckl JR (2001) Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem 276, 4129341300.
  • 24
    Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR & Flier JS (2001) A transgenic model of visceral obesity and the metabolic syndrome. Science 294, 21662170.
  • 25
    Engeli S, Bohnke J, Feldpausch M, Gorzelniak K, Heintze U, Janke J, Luft FC & Sharma AM (2004) Regulation of 11beta-HSD genes in human adipose tissue: influence of central obesity and weight loss. Obes Res 12, 917.
  • 26
    Valsamakis G, Anwar A, Tomlinson JW, Shackleton CH, McTernan PG, Chetty R, Wood PJ, Banerjee AK, Holder G, Barnett AH et al. (2004) 11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus. J Clin Endocrinol Metab 89, 47554761.
  • 27
    Schnackenberg CG (2008) 11beta-hydroxysteroid dehydrogenase type 1 inhibitors for metabolic syndrome. Curr Opin Investig Drugs 9, 295300.
  • 28
    Chrousos GP & Gold PW (1992) The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267, 12441252.
  • 29
    Feinstein R, Kanety H, Papa MZ, Lunenfeld B & Karasik A (1993) Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem 268, 2605526058.
  • 30
    Hotamisligil GS, Shargill NS & Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 8791.
  • 31
    Hotamisligil GS & Spiegelman BM (1994) Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 43, 12711278.
  • 32
    Uysal KT, Wiesbrock SM, Marino MW & Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610614.
  • 33
    Rotter V, Nagaev I & Smith U (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278, 4577745784.
  • 34
    Sartipy P & Loskutoff DJ (2003) Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100, 72657270.
  • 35
    Fried SK, Bunkin DA & Greenberg AS (1998) Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83, 847850.
  • 36
    Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, Yamashita S, Miura M, Fukuda Y, Takemura K et al. (1996) Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med 2, 800803.
  • 37
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL & Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112, 17961808.
  • 38
    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112, 18211830.
  • 39
    Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL & Ferrante AW Jr (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116, 115124.
  • 40
    Lumeng CN, DelProposto JB, Westcott DJ & Saltiel AR (2008) Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57, 32393246.
  • 41
    Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW et al. (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447, 11161120.
  • 42
    Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3, 2335.
  • 43
    Charriere G, Cousin B, Arnaud E, Andre M, Bacou F, Penicaud L & Casteilla L (2003) Preadipocyte conversion to macrophage. Evidence of plasticity. J Biol Chem 278, 98509855.
  • 44
    Chung S, Lapoint K, Martinez K, Kennedy A, Boysen Sandberg M & McIntosh MK (2006) Preadipocytes mediate lipopolysaccharide-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes. Endocrinology 147, 53405351.
  • 45
    Khazen W, M’Bika JP, Tomkiewicz C, Benelli C, Chany C, Achour A & Forest C (2005) Expression of macrophage-selective markers in human and rodent adipocytes. FEBS Lett 579, 56315634.
  • 46
    Kolonin MG, Saha PK, Chan L, Pasqualini R & Arap W (2004) Reversal of obesity by targeted ablation of adipose tissue. Nat Med 10, 625632.
  • 47
    Ghanim H, Mohanty P, Deopurkar R, Sia CL, Korzeniewski K, Abuaysheh S, Chaudhuri A & Dandona P (2008) Acute modulation of toll-like receptors by insulin. Diabetes Care 31, 18271831.
  • 48
    Vitseva OI, Tanriverdi K, Tchkonia TT, Kirkland JL, McDonnell ME, Apovian CM, Freedman J & Gokce N (2008) Inducible Toll-like receptor and NF-kappaB regulatory pathway expression in human adipose tissue. Obesity (Silver Spring) 16, 932937.
  • 49
    Song MJ, Kim KH, Yoon JM & Kim JB (2006) Activation of Toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochem Biophys Res Commun 346, 739745.
  • 50
    Davis JE, Gabler NK, Walker-Daniels J & Spurlock ME (2008) Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity (Silver Spring) 16, 12481255.
  • 51
    Suganami T, Mieda T, Itoh M, Shimoda Y, Kamei Y & Ogawa Y (2007) Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. Biochem Biophys Res Commun 354, 4549.
  • 52
    Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, Araujo EP, Vassallo J, Curi R, Velloso LA et al. (2007) Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56, 19861998.
  • 53
    Abe M, Matsuda M, Kobayashi H, Miyata Y, Nakayama Y, Komuro R, Fukuhara A & Shimomura I (2008) Effects of statins on adipose tissue inflammation: their inhibitory effect on MyD88-independent IRF3/IFN-beta pathway in macrophages. Arterioscler Thromb Vasc Biol 28, 871877.
  • 54
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L & Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425432.
  • 55
    Fantuzzi G (2006) Leptin: nourishment for the immune system. Eur J Immunol 36, 31013104.
  • 56
    La Cava A & Matarese G (2004) The weight of leptin in immunity. Nat Rev Immunol 4, 371379.
  • 57
    Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, Murakami H et al. (2005) Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307, 426430.
  • 58
    Scherer PE, Williams S, Fogliano M, Baldini G & Lodish HF (1995) A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem 270, 2674626749.
  • 59
    Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS & Lazar MA (2001) The hormone resistin links obesity to diabetes. Nature 409, 307312.
  • 60
    Zorad S, Dou JT, Benicky J, Hutanu D, Tybitanclova K, Zhou J & Saavedra JM (2006) Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma. Eur J Pharmacol 552, 112122.
  • 61
    Kos K, Harte AL, James S, Snead DR, O’Hare JP, McTernan PG & Kumar S (2007) Secretion of neuropeptide Y in human adipose tissue and its role in maintenance of adipose tissue mass. Am J Physiol Endocrinol Metab 293, E1335E1340.
  • 62
    Yang K, Guan H, Arany E, Hill DJ & Cao X (2008) Neuropeptide Y is produced in visceral adipose tissue and promotes proliferation of adipocyte precursor cells via the Y1 receptor. FASEB J 22, 24522464.
  • 63
    Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R et al. (2007) Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med 13, 803811.
  • 64
    Digby JE, Chen J, Tang JY, Lehnert H, Matthews RN & Randeva HS (2006) Orexin receptor expression in human adipose tissue: effects of orexin-A and orexin-B. J Endocrinol 191, 129136.
  • 65
    Karagiannides I & Pothoulakis C (2007) Obesity, innate immunity and gut inflammation. Curr Opin Gastroenterol 23, 661666.
  • 66
    Vale W, Spiess J, Rivier C & Rivier J (1981) Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 213, 13941397.
  • 67
    Gay J, Kokkotou E, O’Brien M, Pothoulakis C & Karalis KP (2006) Interleukin-6 genetic ablation protects from trinitrobenzene sulfonic acid-induced colitis in mice. Putative effect of antiinflammatory cytokines. Neuroimmunomodulation 13, 114121.
  • 68
    Friedberg M, Zoumakis E, Hiroi N, Bader T, Chrousos GP & Hochberg Z (2003) Modulation of 11 beta-hydroxysteroid dehydrogenase type 1 in mature human subcutaneous adipocytes by hypothalamic messengers. J Clin Endocrinol Metab 88, 385393.
  • 69
    Seres J, Bornstein SR, Seres P, Willenberg HS, Schulte KM, Scherbaum WA & Ehrhart-Bornstein M (2004) Corticotropin-releasing hormone system in human adipose tissue. J Clin Endocrinol Metab 89, 965970.
  • 70
    Zouboulis CC, Seltmann H, Hiroi N, Chen W, Young M, Oeff M, Scherbaum WA, Orfanos CE, McCann SM & Bornstein SR (2002) Corticotropin-releasing hormone: an autocrine hormone that promotes lipogenesis in human sebocytes. Proc Natl Acad Sci USA 99, 71487153.
  • 71
    Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF & Spiegelman BM (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271, 665668.
  • 72
    Aguirre A, Lopez T, Lopez-Bayghen E & Ortega A (2000) Glutamate regulates kainate-binding protein expression in cultured chick Bergmann glia through an activator protein-1 binding site. J Biol Chem 275, 3924639253.
  • 73
    Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M & Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420, 333336.
  • 74
    Kaneto H, Nakatani Y, Miyatsuka T, Kawamori D, Matsuoka TA, Matsuhisa M, Kajimoto Y, Ichijo H, Yamasaki Y & Hori M (2004) Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nat Med 10, 11281132.
  • 75
    Vallerie SN, Furuhashi M, Fucho R & Hotamisligil GS (2008) A predominant role for parenchymal c-Jun amino terminal kinase (JNK) in the regulation of systemic insulin sensitivity. PLoS ONE 3, e3151.
  • 76
    Hotamisligil GS & Erbay E (2008) Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 8, 923934.
  • 77
    Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J & Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11, 191198.
  • 78
    Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, Grivennikov S, Wynshaw-Boris A, Scadeng M, Olefsky JM et al. (2007) JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab 6, 386397.
  • 79
    Makowski L, Brittingham KC, Reynolds JM, Suttles J & Hotamisligil GS (2005) The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. J Biol Chem 280, 1288812895.
  • 80
    Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, Rimm EB & Hotamisligil GS (2006) A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease. Proc Natl Acad Sci USA 103, 69706975.
  • 81
    Houstis N, Rosen ED & Lander ES (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944948.
  • 82
    Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, Saunders T, Bonner-Weir S & Kaufman RJ (2001) Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell 7, 11651176.
  • 83
    Ron D & Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8, 519529.
  • 84
    Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP & Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664666.
  • 85
    Ozawa K, Miyazaki M, Matsuhisa M, Takano K, Nakatani Y, Hatazaki M, Tamatani T, Yamagata K, Miyagawa J, Kitao Y et al. (2005) The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes. Diabetes 54, 657663.
  • 86
    Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ & Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 11371140.
  • 87
    Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers MG Jr & Ozcan U (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9, 3551.
  • 88
    Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T & Donath MY (2007) Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 356, 15171526.
  • 89
    Goldfine AB, Silver R, Aldhahi W, Cai D, Tatro E, Lee J & Shoelson SE (2008) Use of Salsalate to Target Inflammation in the Treatment of Insulin Resistance and Type 2 Diabetes. Clin Transl Sci 1, 3643.
  • 90
    Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, Zhang C, Lamb J, Edwards S, Sieberts SK et al. (2008) Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429435.
  • 91
    Emilsson V, Thorleifsson G, Zhang B, Leonardson AS, Zink F, Zhu J, Carlson S, Helgason A, Walters GB, Gunnarsdottir S et al. (2008) Genetics of gene expression and its effect on disease. Nature 452, 423428.