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[交流] STM：靶向作用脂肪激素或可开发出治疗2型糖尿病的新型疗法

12月23日，来自哈佛大学的一个研究团队通过研究描述了一种临床前的方法或可帮助治疗2型糖尿病、脂肪肝及其它代谢性疾病，文章中研究者开发了一种抗体，其可以改善通过靶向作用脂肪组织中名为aP2（FABP4）的激素来帮助改善机体的葡萄糖调节，并且降低肥胖小鼠集体的脂肪肝症状。
Development of a therapeutic monoclonal antibody that targets secreted fatty acid–binding protein aP2 to treat type 2 diabetes
http://stm.sciencemag.org/content/7/319/319ra205

Kill the messenger

A variety of metabolic messengers—many from adipose tissue itself—controls the energy state of organs and organisms. Recently, researchers showed that the fatty acid binding protein aP2, once thought to live and work only in the cytoplasm, is also secreted by adipose tissue and spurs metabolic changes in other organs. Now, Burak and colleagues test whether secreted aP2 can serve as a therapeutic target for type 2 diabetes.

In mice, the secreted form of aP2 regulates glucose production in liver, systemic glucose homeostasis, and insulin resistance. Serum levels of aP2 were shown to be elevated in obese mice and humans and to correlate with metabolic complications. The authors identified a monoclonal antibody to aP2 that lowered fasting blood glucose, increased insulin sensitivity, and lowered both fat mass and fatty liver (steatosis) in obese mouse models, relative to a control antibody, but not in aP2-deficient mice. The antidiabetic effects of the therapeutic antibody were linked to the regulation of hepatic glucose output and peripheral glucose utilization. Together, these findings suggest that an aP2-targeted antibody that kills the messenger is a viable approach for diabetes treatment.

Abstract

The lipid chaperone aP2/FABP4 has been implicated in the pathology of many immunometabolic diseases, including diabetes in humans, but aP2 has not yet been targeted for therapeutic applications. aP2 is not only an intracellular protein but also an active adipokine that contributes to hyperglycemia by promoting hepatic gluconeogenesis and interfering with peripheral insulin action. Serum aP2 levels are markedly elevated in mouse and human obesity and strongly correlate with metabolic complications. These observations raise the possibility of a new strategy to treat metabolic disease by targeting serum aP2 with a monoclonal antibody (mAb) to aP2. We evaluated mAbs to aP2 and identified one, CA33, that lowered fasting blood glucose, improved systemic glucose metabolism, increased systemic insulin sensitivity, and reduced fat mass and liver steatosis in obese mouse models. We examined the structure of the aP2-CA33 complex and resolved the target epitope by crystallographic studies in comparison to another mAb that lacked efficacy in vivo. In hyperinsulinemic-euglycemic clamp studies, we found that the antidiabetic effect of CA33 was predominantly linked to the regulation of hepatic glucose output and peripheral glucose utilization. The antibody had no effect in aP2-deficient mice, demonstrating its target specificity. We conclude that an aP2 mAb–mediated therapeutic constitutes a feasible approach for the treatment of diabetes.

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