Wnt10b Inhibits Obesity in ob/ob and Agouti Mice

Wnt10b Inhibits Obesity in ob/ob and Agouti Mice Wendy S. Wright 1 , Kenneth A. Longo 1 , Vernon W. Dolinsky 1 , Isabelle Gerin 1 , Sona Kang 1 , Christina N. Bennett 1 , Shian-Huey Chiang 1 , Tyler C. Prestwich 1 , Catherine Gress 2 , Charles F. Burant 1 3 , Vedrana S. Susulic 2 and Ormond A. MacDougald 1 3 1 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 2 Centocor, Horsham, Pennsylvania 3 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan Address correspondence and reprint requests to Ormond A. MacDougald, Department of Molecular and Integrative Physiology, 7620 Medical Science II, 1301 E. Catherine Dr., Ann Arbor, MI 48109-0622. E-mail: macdouga{at}umich.edu Abstract The Wnt family of secreted signaling molecules has profound effects on diverse developmental processes, including the fate of mesenchymal progenitors. While activation of Wnt signaling blocks adipogenesis, inhibition of endogenous Wnt/β-catenin signaling by Wnt10b promotes spontaneous preadipocyte differentiation. Transgenic mice with expression of Wnt10b from the FABP4 promoter (FABP4-Wnt10b) have less adipose tissue when maintained on a normal chow diet and are resistant to diet-induced obesity. Here we demonstrate that FABP4-Wnt10b mice largely avert weight gain and metabolic abnormalities associated with genetic obesity. FABP4-Wnt10b mice do not gain significant body weight on the ob/ob background, and at 8 weeks of age, they have an ∼70% reduction in visceral and subcutaneous adipose tissues compared with ob/ob mice. Similarly, on the lethal yellow agouti ( A y ) background, FABP4-Wnt10b mice have 50–70% less adipose tissue weight and circulating leptin at 5 months of age. Wnt10b- Ay mice are more glucose tolerant and insulin sensitive than A y controls, perhaps due to reduced expression and circulation of resistin. Reduced expression of inflammatory cytokines may also contribute to improved glucose homeostasis. DEXA, dual-energy X-ray absorptiometry iNOS, inducible nitric oxide synthase MCP, monocyte chemotactic protein TNF, tumor necrosis factor Footnotes W.S.W. and K.A.L. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted November 1, 2006. Received September 25, 2006. DIABETES