Covey Scott D, Wideman Rhonda D, McDonald Christine, Unniappan Suraj, Huynh Frank, Asadi Ali, Speck Madeleine, Webber Travis, Chua Streamson C, Kieffer Timothy J
Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
Cell Metab. 2006 Oct;4(4):291-302. doi: 10.1016/j.cmet.2006.09.005.
The hormone leptin plays a crucial role in maintenance of body weight and glucose homeostasis. This occurs through central and peripheral pathways, including regulation of insulin secretion by pancreatic beta cells. To study this further in mice, we disrupted the signaling domain of the leptin receptor gene in beta cells and hypothalamus. These mice develop obesity, fasting hyperinsulinemia, impaired glucose-stimulated insulin release, and glucose intolerance, similar to leptin receptor null mice. However, whereas complete loss of leptin function causes increased food intake, this tissue-specific attenuation of leptin signaling does not alter food intake or satiety responses to leptin. Moreover, unlike other obese models, these mice have reduced fasting blood glucose. These results indicate that leptin regulation of glucose homeostasis extends beyond insulin sensitivity to influence beta cell function, independent of pathways controlling food intake. These data suggest that defects in this adipoinsular axis could contribute to diabetes associated with obesity.
激素瘦素在维持体重和葡萄糖稳态方面起着至关重要的作用。这是通过中枢和外周途径实现的，包括胰腺β细胞对胰岛素分泌的调节。为了在小鼠中进一步研究这一点，我们破坏了β细胞和下丘脑中瘦素受体基因的信号域。这些小鼠会出现肥胖、空腹高胰岛素血症、葡萄糖刺激的胰岛素释放受损以及葡萄糖不耐受，类似于瘦素受体缺失小鼠。然而，虽然瘦素功能的完全丧失会导致食物摄入量增加，但这种瘦素信号的组织特异性减弱并不会改变食物摄入量或对瘦素的饱腹感反应。此外，与其他肥胖模型不同，这些小鼠的空腹血糖降低。这些结果表明，瘦素对葡萄糖稳态的调节不仅限于胰岛素敏感性，还能独立于控制食物摄入的途径来影响β细胞功能。这些数据表明，这个脂肪胰岛轴的缺陷可能导致与肥胖相关的糖尿病。
