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Adipokines: inflammation and the pleiotropic role of white adipose tissue

Published online by Cambridge University Press:  09 March 2007

Paul Trayhurn  and
I. Stuart Wood
Paul Trayhurn*
Affiliation:
Neuroendocrine and Obesity Biology Unit, Liverpool Centre for Nutritional Genomics, School of Clinical Sciences, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK
I. Stuart Wood
Affiliation:
Neuroendocrine and Obesity Biology Unit, Liverpool Centre for Nutritional Genomics, School of Clinical Sciences, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK
*
*Corresponding author: fax +44 151 706 5802, Email p.trayhurn@liverpool.ac.uk
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Abstract

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White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endocrine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various protein signals have been given the collective name ‘adipocytokines’ or ‘adipokines’. However, since most are neither ‘cytokines’ nor ‘cytokine-like’, it is recommended that the term ‘adipokine’ be universally adopted to describe a protein that is secreted from (and synthesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only by the other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fatty acids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance. In addition, there is a growing list of adipokines involved in inflammation (TNFα, IL-1β, IL-6, IL-8, IL-10, transforming growth factor-β, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Production of these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatory cytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally to insulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively to the elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimonious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates primarily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growing adipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcription factor hypoxia inducible factor-1.

Keywords

White adipose tissueAdipokinesInflammationObesityHypoxiaCytokinesAcute phase proteins
Type
Horizons in Nutritional Science
Information
British Journal of Nutrition , Volume 92 , Issue 3 , September 2004 , pp. 347 - 355
Copyright
Copyright © The Nutrition Society 2004

References

Ahima, RS, Prabakaran, D, Mantzoros, C, Qu, DQ, Lowell, B, Maratos-Flier, E & Flier, JSRole of leptin in the neuroendocrine response to fasting. Nature (1996) 382, 250–252.CrossRefGoogle Scholar
Alessi, MC & Bastelica, D, Morange, P, Berthet, B, Leduc, I, Verdier, M, Geel, O & Juhan-Vague, IPlasminogen activator inhibitor 1, TGFβ1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes (2000) 49, 1374–1380.CrossRefGoogle Scholar
Ambrosini, G, Nath, AK, Sierra-Honigmann, MR & Flores-Riveros, JTranscriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1. J Biol Chem (2002) 277, 34601–34609.CrossRefGoogle ScholarPubMed
Arita, Y, Kihara, S & Ouchi, NParadoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun (1999) 257, 79–83.CrossRefGoogle ScholarPubMed
Bastard, JP, Jardel, C, Bruckert, E, Blondy, P, Capeau, J, Laville, M, Vidal, H & Hainque, BElevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J Clin Endocrinol Metab (2000) 85, 3338–3342.Google ScholarPubMed
Berg, AH, Combs, TP, Du, X, Brownlee, M & Scherer, PEThe adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nature Med (2001) 7, 947–953.CrossRefGoogle ScholarPubMed
Binley, K, Kan, O, White, J & Naylor, SExploiting the hypoxia response. Curr Opin Mol Ther (2003) 5, 650–656.Google ScholarPubMed
Bruun, JM, Pedersen, SB & Richelsen, BInterleukin-8 production in human adipose tissue. Inhibitory effects of anti-diabetic compounds, the thiazolidinedione ciglitazone and the biguanide metformin. Horm Metab Res (2000) 32, 537–541.CrossRefGoogle ScholarPubMed
Bruun, JM, Pedersen, SB & Richelsen, BRegulation of interleukin 8 production and gene expression in human adipose tissue in vitro. J Clin Endocrinol Metab (2001) 86, 1267–1273.Google ScholarPubMed
Bulló, M, Garcia-Lorda, P, Megias, I & Salas-Salvado, JSystemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obesity Res (2003) 11, 525–531.CrossRefGoogle ScholarPubMed
Chaldakov, GN, Stankulov, IS, Fiore, M, Ghenev, PI & Aloe, LNerve growth factor levels and mast cell distribution in human coronary atherosclerosis. Atherosclerosis (2001) 159, 57–66.CrossRefGoogle ScholarPubMed
Chiellini, C, Bertacca, A & Novelli, SEObesity modulates the expression of haptoglobin in the white adipose tissue via TNFα. J Cell Physiol (2002) 190, 251–258.CrossRefGoogle ScholarPubMed
Chinetti, G, Fruchart, JC & Staels, BPeroxisome proliferator-activated receptors and inflammation: from basic science to clinical applications. Int J Obesity (2003) 27, Suppl. 3 S41–S45.CrossRefGoogle ScholarPubMed
Cigolini, M, Tonoli, M & Borgato, LExpression of plasminogen activator inhibitor-1 in human adipose tissue: a role for TNF-α?. Atherosclerosis (1999) 143, 81–90.CrossRefGoogle ScholarPubMed
Claffey, KP, Wilkison, WO & Spiegelman, BMVascular endothelial growth factor. Regulation by cell differentiation and activated second messenger pathways. J Biol Chem (1992) 267, 16317–16322.Google ScholarPubMed
Cook, KS, Groves, DL, Min, HY & Spiegelman, BMA developmentally regulated mRNA from 3T3 adipocytes encodes a novel serine protease homologue. Proc Natl Acad Sci USA (1985) 82, 6480–6484.CrossRefGoogle ScholarPubMed
Cook, KS, Min, HY, Johnson, D, Chaplinsky, RJ, Flier, JS, Hunt, CR & Spiegelman, BMAdipsin: a circulating serine protease homolog secreted by adipose tissue and sciatic nerve. Science (1987) 237, 402–405.CrossRefGoogle ScholarPubMed
Coppack, SWPro-inflammatory cytokines and adipose tissue. Proc Nutr Soc (2001) 60, 349–356.CrossRefGoogle ScholarPubMed
Das, UNIs obesity an inflammatory condition?. Nutrition (2001) 17, 953–966.CrossRefGoogle ScholarPubMed
Dietze, D, Koenen, M, Rohrig, K, Horikoshi, H, Hauner, H & Eckel, JImpairment of insulin signaling in human skeletal muscle cells by co-culture with human adipocytes. Diabetes (2002) 51, 2369–2376.CrossRefGoogle ScholarPubMed
Ehrhart-Bornstein, M, Lamounier-Zepter, V, Schraven, A, Langenbach, J, Willenberg, HS, Barthel, A, Hauner, H, McCann, SM, Scherbaum, WA & Bornstein, SRHuman adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci USA (2003) 100, 14211–14216.CrossRefGoogle ScholarPubMed
Engeli, S, Feldpausch, M, Gorzelniak, K, Hartwig, F, Heintze, U, Janke, J, Mohlig, M, Pfeiffer, AFH, Luft, FC & Sharma, AMAssociation between adiponectin and mediators of inflammation in obese women. Diabetes (2003) 52, 942–947.CrossRefGoogle ScholarPubMed
Engström, G, Hedblad, B, Stavenow, L, Lind, P, Janzon, L & Lindgärde, FInflammation-sensitive plasma proteins are associated with future weight gain. Diabetes (2003) 52, 2097–2101.CrossRefGoogle ScholarPubMed
Eriksson, P, Reynisdottir, S, Lonnqvist, F, Stemme, V, Hamsten, A & Arner, PAdipose tissue secretion of plasminogen activator inhibitor-1 in non-obese and obese individuals. Diabetologia (1998) 41, 65–71.CrossRefGoogle ScholarPubMed
Esposito, K, Pontillo, A, Ciotola, M, Di Palo, C, Grella, E, Nicoletti, G & Giugliano, DWeight loss reduces interleukin-18 levels in obese women. J Clin Endocrinol Metab (2002) 87, 3864–3866.CrossRefGoogle ScholarPubMed
Esposito, K, Pontillo, A, Giugliano, F, Giugliano, G, Marfella, R, Nicoletti, G & Giugliano, DAssociation of low interleukin-10 levels with the metabolic syndrome in obese women. J Clin Endocrinol Metab (2003) 88, 1055–1058.CrossRefGoogle ScholarPubMed
Fain, JN, Bahouth, SW & Madan, AKHaptoglobin release by human adipose tissue in primary culture. J Lipid Res (2004 a) 45, 536–542.CrossRefGoogle ScholarPubMed
Fain, JN, Madan, AK, Hiler, ML, Cheema, P & Bahouth, SWComparison 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 b) 145, 2273–2282.CrossRefGoogle ScholarPubMed
Festa, A, D'Agostino, R Jr, Williams, K, Karter, AJ, Mayer-Davis, EJ, Tracy, RP & Haffner, SMThe relation of body fat mass and distribution to markers of chronic inflammation. Int J Obesity (2001) 25, 1407–1415.CrossRefGoogle ScholarPubMed
Friedrichs, WE, Navarijo-Ashbaugh, AL, Bowman, BH & Yang, FExpression and inflammatory regulation of haptoglobin gene in adipocytes. Biochem Biophys Res Commun (1995) 209, 250–256.CrossRefGoogle ScholarPubMed
Frühbeck, G, Gómez-Ambrosi, J, Muruzabal, FJ & Burrell, MAThe adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol (2001) 280, E827–E847.Google ScholarPubMed
Funahashi, T, Nakamura, T, Shimomura, I, Maeda, K, Kuriyama, H, Takahashi, M, Arita, Y, Kihara, S & Matsuzawa, YRole of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Intern Med (1999) 38, 202–206.CrossRefGoogle ScholarPubMed
Gabay, C & Kushner, IAcute-phase proteins and other systemic responses to inflammation. New Engl J Med (1999) 340, 448–454.CrossRefGoogle ScholarPubMed
Hasan, W, Zhang, R, Liu, M, Warn, JD & Smith, PGCoordinate expression of NGF and alpha-smooth muscle actin mRNA and protein in cutaneous wound tissue of developing and adult rats. Cell Tissue Res (2000) 300, 97–109.Google ScholarPubMed
Heinrich, PC, Castell, JV & Andus, TInterleukin-6 and the acute phase response. Biochem J (1990) 265, 621–636.CrossRefGoogle ScholarPubMed
Hellwig-Bürgel, T, Rutkowski, K, Metzen, E, Fandrey, J & Jelkmann, WInterleukin-1β and tumor necrosis factor-α stimulate DNA binding of hypoxia-inducible factor-1. Blood (1999) 94, 1561–1567.Google ScholarPubMed
Höpfl, G, Ogunshola, O & Gassmann, MHIFs and tumors - causes and consequences. Am J Physiol (2004) 286, R608–R623.Google ScholarPubMed
Hotamisligil, GSInflammatory pathways and insulin action. Int J Obesity, (2003) 27, Suppl. 3. S53–S55.CrossRefGoogle ScholarPubMed
Hotamisligil, GS, Shargill, NS & Spiegelman, BMAdipose expression of tumor necrosis factor-alpha - direct role in obesity-linked insulin resistance. Science (1993) 259, 87–91.CrossRefGoogle ScholarPubMed
Hotta, K, Funahashi, T & Arita, YPlasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscl Thromb Vasc Biol (2000) 20, 1595–1599.CrossRefGoogle ScholarPubMed
Kersten, S, Mandard, S, Tan, NS, Escher, P, Metzger, D, Chambon, P, Gonzalez, FJ, Desvergne, B & Wahli, WCharacterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem (2000) 275, 28488–28493.CrossRefGoogle ScholarPubMed
Klaus, SAdipose tissue as a regulator of energy balance. Curr Drug Targets (2004) 4, 1–10.Google Scholar
Kratchmarova, I, Kalume, DE & Blagoev, BA proteomic approach for identification of secreted proteins during the differentiation of 3T3-L1 preadipocytes to adipocytes. Mol Cell Proteomics (2002) 1, 213–222.CrossRefGoogle ScholarPubMed
Levi-Montalcini, R, Skaper, SD, Dal Toso, R, Petrelli, L & Leon, ANerve growth factor: from neurotrophin to neurokine. Trends Neurosci (1996) 19, 514–520.CrossRefGoogle ScholarPubMed
Lin, Y, Rajala, MW, Berger, JP, Moller, DE, Barzilai, N & Scherer, PEHyperglycemia-induced production of acute phase reactants in adipose tissue. J Biol Chem (2001) 276, 42077–42083.CrossRefGoogle ScholarPubMed
Lolmede, K, Durand, de, Saint Front, V, Galitzky, J, Lafontan, M & Bouloumie, AEffects of hypoxia on the expression of proangiogenic factors in differentiated 3T3-F442A adipocytes. Int J Obesity (2003) 27, 1187–1195.CrossRefGoogle ScholarPubMed
Lundgren, CH, Brown, SL, Nordt, TK, Sobel, BE & Fujii, SElaboration of type-1 plasminogen activator inhibitor from adipocytes - a potential pathogenetic link between obesity and cardiovascular disease. Circulation (1996) 93, 106–110.CrossRefGoogle ScholarPubMed
Mohamed-Ali, V, Goodrick, S, Rawesh, A, Katz, DR, Miles, JM, Yudkin, JS, Klein, S & Coppack, SWSubcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J Clin Endocrinol Metab (1997) 82, 4196–4200.Google Scholar
Mohamed-Ali, V, Pinkney, JH & Coppack, SWAdipose tissue as an endocrine and paracrine organ. Int J Obesity (1998) 22, 1145–1158.CrossRefGoogle ScholarPubMed
Moller, DE & Berger, JPRole of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. Int J Obesity (2003) 27, Suppl. 3 S17–S21.CrossRefGoogle ScholarPubMed
Mutch, NJ, Wilson, HM & Booth, NAPlasminogen activator inhibitor-1 and haemostasis in obesity. Proc Nutr Soc (2001) 60, 341–347.CrossRefGoogle ScholarPubMed
Oller, do, Nascimento, C, Hunter, L & Trayhurn, PRegulation of haptoglobin gene expression in 3T3-L1 adipocytes by cytokines, catecholamines, and PPARγ. Biochem Biophys Res Commun (2004) 313, 702–708.CrossRefGoogle Scholar
Ouchi, N, Kihara, S & Arita, YNovel modulator for endothelial adhesion molecules - adipocyte-derived plasma protein adiponectin. Circulation (1999) 100, 2473–2476.CrossRefGoogle ScholarPubMed
Ouchi, N, Kihara, S & Funahashi, TReciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation (2003) 107, 671–674.CrossRefGoogle ScholarPubMed
Pannacciulli, N, Cantatore, FP, Minenna, A, Bellacicco, M, Giorgino, R & De Pergola, GC-reactive protein is independently associated with total body fat, central fat, and insulin resistance in adult women. Int J Obesity (2001) 25, 1416–1420.CrossRefGoogle ScholarPubMed
Peeraully, MR, Jenkins, JR & Trayhurn, PNGF gene expression and secretion in white adipose tissue: regulation in 3T3-L1 adipocytes by hormones and inflammatory cytokines. Am J Physiol (2004) 287 (In the Press).Google ScholarPubMed
Prins, JB, Niesler, CU, Winterford, CM, Bright, NA, Siddle, K, Orahilly, S, Walker, NI & Cameron, DPTumor necrosis factor-alpha induces apoptosis of human adipose cells. Diabetes (1997) 46, 1939–1944.CrossRefGoogle ScholarPubMed
Rajala, MW & Scherer, PEMinireview: the adipocyte - at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology (2003) 144, 3765–3773.CrossRefGoogle ScholarPubMed
Rayner, DV & Trayhurn, PRegulation of leptin production: sympathetic nervous system interactions. J Mol Med (2001) 79, 8–20.CrossRefGoogle ScholarPubMed
Rupnick, MA, Panigrahy, D, Zhang, C-Y, Dallabrida, SM, Lowell, BB, Langer, R & Folkman, MJAdipose tissue mass can be regulated through the vasculature. Proc Natl Acad Sci USA (2002) 99, 10730–10735.CrossRefGoogle ScholarPubMed
Samad, F, Yamamoto, K & Loskutoff, DJDistribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo - induction by tumor necrosis factor-α and lipopolysaccharide. J Clin Invest (1996) 97, 37–46.CrossRefGoogle ScholarPubMed
Semenza, GLHIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol (2001) 13, 167–171.CrossRefGoogle ScholarPubMed
Soukas, A, Cohen, P, Socci, ND & Friedman, JMLeptin-specific patterns of gene expression in white adipose tissue. Genes Dev (2000) 14, 963–980.Google ScholarPubMed
Starnes, T, Broxmeyer, HE, Robertson, MJ & Hromas, RCutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J Immunol (2002) 169, 642–646.CrossRefGoogle ScholarPubMed
Straczkowski, M, Dzienis-Straczkowska, S, Stepien, A, Kowalska, I, Szelachowska, M & Kinalska, IPlasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-α system. J Clin Endocrinol Metab (2002) 87, 4602–4606.CrossRefGoogle ScholarPubMed
Tchernof, A, Nolan, A, Sites, CK, Ades, PA & Poehlman, ETWeight loss reduces C-reactive protein levels in obese postmenopausal women. Circulation (2002) 105, 564–569.CrossRefGoogle ScholarPubMed
Trayhurn, P & Beattie, JHPhysiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc (2001) 60, 329–339.CrossRefGoogle ScholarPubMed
Uhlar, CM & Whitehead, ASSerum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem (1999) 265, 501–523.CrossRefGoogle ScholarPubMed
Vega, JA, Garcia-Suarez, O, Hannestad, J, Perez-Perez, M & Germana, ANeurotrophins and the immune system. J Anat (2003) 203, 1–19.CrossRefGoogle ScholarPubMed
Visser, M, Bouter, LM, McQuillan, GM, Wener, MH & Harris, TBElevated C-reactive protein levels in overweight and obese adults. J Am Med Assoc (1999) 282, 2131–2135.CrossRefGoogle ScholarPubMed
Volanakis, JEHuman C-reactive protein: expression, structure, and function. Mol Immunol (2001) 38, 189–197.CrossRefGoogle ScholarPubMed
Vozarova, B, Weyer, C, Hanson, K, Tataranni, PA, Bogardus, C & Pratley, RECirculating interleukin-6 in relation to adiposity, insulin action, and insulin secretion. Obesity Res (2001) 9, 414–417.CrossRefGoogle ScholarPubMed
Wallenius, K, Wallenius, V, Sunter, D, Dickson, SL & Jansson, JOIntracerebroventricular interleukin-6 treatment decreases body fat in rats. Biochem Biophys Res Commun (2002) 293, 560–565.CrossRefGoogle ScholarPubMed
Weisberg, SP, McCann, D, Desai, M, Rosenbaum, M, Leibel, RL & Ferrante, AW JrObesity is associated with macrophage accumulation in adipose tissue. J Clin Invest (2003) 112, 1796–1808.CrossRefGoogle ScholarPubMed
Wenger, RHCellular adaptation to hypoxia: O 2 -sensing protein hydroxylases, hypoxia-inducible transcription factors, and O 2 -regulated gene expression. FASEB J (2002) 16, 1151–1162.CrossRefGoogle Scholar
Wiesner, G, Morash, BA, Ur, E & Wilkinson, MFood restriction regulates adipose-specific cytokines in pituitary gland but not in hypothalamus. J Endocrinol (2004) 180, R1–R6.CrossRefGoogle ScholarPubMed
Xu, H, Barnes, GT & Yang, QChronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest (2003) 112, 1821–1830.CrossRefGoogle Scholar
Yamauchi, T, Kamon, J & Waki, HThe fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Med (2001) 7, 941–946.CrossRefGoogle ScholarPubMed
Yang, YS, Song, HD, Li, RY, Zhou, LB, Zhu, ZD, Hu, RM, Han, ZG & Chen, JLThe gene expression profiling of human visceral adipose tissue and its secretory functions. Biochem Biophys Res Commun (2003) 300, 839–846.CrossRefGoogle ScholarPubMed
Yokota, T, Oritani, K & Takahashi, IAdiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood (2000) 96, 1723–1732.Google ScholarPubMed
Yoon, JC, Chickering, TW, Rosen, ED, Dussault, B, Qin, Y, Soukas, A, Friedman, JM, Holmes, WE & Spiegelman, BMPeroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation. Mol Cell Biol (2000) 20, 5343–5349.CrossRefGoogle ScholarPubMed
Yudkin, JSAdipose tissue, insulin action and vascular disease: inflammatory signals. Int J Obesity (2003) 27 Suppl. 3, S25–S28.CrossRefGoogle ScholarPubMed
Yudkin, JS, Kumari, M, Humphries, SE & Mohamed-Ali, VInflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. Atherosclerosis (2000) 148, 209–214.CrossRefGoogle ScholarPubMed
Yudkin, JS, Stehouwer, CD, Emeis, JJ & Coppack, SWC-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?. Arterioscler Thromb Vasc Biol (1999) 19, 972–978.CrossRefGoogle ScholarPubMed
Zhang, YY, Proenca, R, Maffei, M, Barone, M, Leopold, L & Friedman, JMPositional cloning of the mouse obese gene and its human homolog. Nature (1994) 372, 425–432.CrossRefGoogle Scholar