IGF-Binding Protein-2 Protects Against the Development of Obesity and Insulin Resistance

IGF-Binding Protein-2 Protects Against the Development of Obesity and Insulin Resistance Stephen B. Wheatcroft 1 , Mark T. Kearney 1 , Ajay M. Shah 2 , Vivienne A. Ezzat 2 , John R. Miell 2 , Michael Modo 3 , Stephen C.R. Williams 3 , Will P. Cawthorn 4 , Gema Medina-Gomez 4 , Antonio Vidal-Puig 4 , Jaswinder K. Sethi 4 and Paul A. Crossey 5 1 Diabetes and Cardiovascular Research in Leeds, The LIGHT Laboratories, University of Leeds, U.K 2 Cardiovascular Division, King’s College London, U.K 3 Institute of Psychiatry, King’s College London, U.K 4 Department of Clinical Biochemistry, University of Cambridge, Cambridge, U.K 5 School of Biomedical and Molecular Sciences, University of Surrey, U.K Address correspondence and reprint requests to Prof. Mark Kearney, Academic Unit of Cardiovascular Medicine, The LIGHT Laboratories, Clarendon Way, University of Leeds, Leeds, LS2 9JT, U.K. E-mail: m.t.kearney{at}leeds.ac.uk Abstract Proliferation of adipocyte precursors and their differentiation into mature adipocytes contributes to the development of obesity in mammals. IGF-I is a potent mitogen and important stimulus for adipocyte differentiation. The biological actions of IGFs are closely regulated by a family of IGF-binding proteins (IGFBPs), which exert predominantly inhibitory effects. IGFBP-2 is the principal binding protein secreted by differentiating white preadipocytes, suggesting a potential role in the development of obesity. We have generated transgenic mice overexpressing human IGFBP-2 under the control of its native promoter, and we show that overexpression of IGFBP-2 is associated with reduced susceptibility to obesity and improved insulin sensitivity. Whereas wild-type littermates developed glucose intolerance and increased blood pressure with aging, mice overexpressing IGFBP-2 were protected. Furthermore, when fed a high-fat/high-energy diet, IGFBP-2–overexpressing mice were resistant to the development of obesity and insulin resistance. This lean phenotype was associated with decreased leptin levels, increased glucose sensitivity, and lower blood pressure compared with wild-type animals consuming similar amounts of high-fat diet. Our in vitro data suggest a direct effect of IGFBP-2 preventing adipogenesis as indicated by the ability of recombinant IGFBP-2 to impair 3T3-L1 differentiation. These findings suggest an important, novel role for IGFBP-2 in obesity prevention. BBSRC, Biotechnology and Biological Sciences Research Council BHF, British Hear