Cell Metab：挑战常规，小鼠研究证实胰岛素导致肥胖

当吃得太多时，因体内长期含有高水平胰岛素，我们可能变得肥胖。根据一项新的研究，研究人员发现高水平的胰岛素导致小鼠变胖，这一发现挑战了一个普遍持有的观点：水平增加的胰岛素是肥胖和胰岛素耐受性的次级后果。相关研究结果于12月4日发表在Cell Metabolism期刊上。

这项新研究有助于解决这个先有鸡还是先有蛋的难题，因为它证实持续保持低水平胰岛素的动物即便放纵地吃富含高脂肪的食物仍然保持苗条。这些研究发现是首次在哺乳动物体内证实血液中循环的胰岛素能够导致肥胖。

加拿大不列颠哥伦比亚大学研究员James Johnson说，这些研究结果也与临床研究证实糖尿病患者长期使用胰岛素往往会导致他们的体重增加。

在这项研究中，Johnson和他的同事们利用小鼠的一种基因变异：它们拥有两个胰岛素基因。基因Insulin1主要出现在胰腺中，而基因insulin2在胰腺和大脑中都存在。通过移除insulin2和改变insulin1基因拷贝数目，研究人员培养出只有空腹血胰岛素水平发生变化的小鼠。当给它们喂食富含高脂肪食物时，含有一个insulin1基因拷贝且保持较低水平空腹胰岛素的小鼠完全不会变得肥胖，甚至不会产生任何食物不振。它们也产生较低水平的炎症，并且它们的肝脏含有较少的脂肪。

尽管用来阻断胰岛素的药物会产生不想要的副作用，但是到目前为止，这并不意味着这些研究发现可能能够用于诊所治疗中。

doi: 10.1016/j.cmet.2012.10.019
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Hyperinsulinemia Drives Diet-Induced Obesity Independently of Brain Insulin Production

Arya E. Mehran, Nicole M. Templeman, G. Stefano Brigidi, Gareth E. Lim, Kwan-Yi Chu, Xiaoke Hu, Jose Diego Botezelli, Ali Asadi, Bradford G. Hoffman, Timothy J. Kieffer, Shernaz X. Bamji, Susanne M. Clee, James D. Johnson

Hyperinsulinemia is associated with obesity and pancreatic islet hyperplasia, but whether insulin causes these phenomena or is a compensatory response has remained unsettled for decades. We examined the role of insulin hypersecretion in diet-induced obesity by varying the pancreas-specific Ins1 gene dosage in mice lacking Ins2 gene expression in the pancreas, thymus, and brain. Age-dependent increases in fasting insulin and β cell mass were absent in Ins1+/−:Ins2−/− mice fed a high-fat diet when compared to Ins1+/+:Ins2−/− littermate controls. Remarkably, Ins1+/−:Ins2−/− mice were completely protected from diet-induced obesity. Genetic prevention of chronic hyperinsulinemia in this model reprogrammed white adipose tissue to express uncoupling protein 1 and increase energy expenditure. Normalization of adipocyte size and activation of energy expenditure genes in white adipose tissue was associated with reduced inflammation, reduced fatty acid spillover, and reduced hepatic steatosis. Thus, we provide genetic evidence that pathological circulating hyperinsulinemia drives diet-induced obesity and its complications.