Wright Wendy S, Longo Kenneth A, Dolinsky Vernon W, Gerin Isabelle, Kang Sona, Bennett Christina N, Chiang Shian-Huey, Prestwich Tyler C, Gress Catherine, Burant Charles F, Susulic Vedrana S, MacDougald Ormond A
Department of Molecular and Integrative Physiology, University of Michigan, 1301 E. Catherine Drive, Ann Arbor, MI 48109-0622, USA.
Diabetes. 2007 Feb;56(2):295-303. doi: 10.2337/db06-1339.
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/beta-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 approximately 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.
分泌型信号分子Wnt家族对多种发育过程具有深远影响，包括间充质祖细胞的命运。虽然Wnt信号的激活会阻断脂肪生成，但Wnt10b对内源性Wnt/β-连环蛋白信号的抑制会促进前脂肪细胞的自发分化。从FABP4启动子表达Wnt10b的转基因小鼠（FABP4-Wnt10b）在正常饮食条件下脂肪组织较少，并且对饮食诱导的肥胖具有抗性。在此我们证明，FABP4-Wnt10b小鼠在很大程度上避免了与遗传性肥胖相关的体重增加和代谢异常。FABP4-Wnt10b小鼠在ob/ob背景下体重没有显著增加，在8周龄时，与ob/ob小鼠相比，它们的内脏和皮下脂肪组织减少了约70%。同样，在致死性黄色刺鼠（A(y)）背景下，FABP4-Wnt10b小鼠在5月龄时脂肪组织重量和循环瘦素减少50 - 70%。Wnt10b-Ay小鼠比A(y)对照更耐葡萄糖且胰岛素敏感性更高，这可能是由于抵抗素的表达和循环减少所致。炎性细胞因子表达的降低也可能有助于改善葡萄糖稳态。
