Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Physiology, Monash University, Victoria 3800, Australia.
Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
Cell Rep. 2019 Jan 8;26(2):346-355.e3. doi: 10.1016/j.celrep.2018.12.061.
Insulin action in the hypothalamus results in the suppression of hepatic glucose production (HGP). Obesity is often associated with a diminished response to insulin, leading to impaired suppression of HGP in obese mice. Here, we demonstrate that blocking central leptin signaling in diet-induced obese (DIO) mice restores the liver's ability to suppress glucose production. Leptin increases the expression of the insulin receptor phosphatase PTP1B, which is highly expressed in the hypothalamus of DIO mice. We demonstrate that the central pharmacological inhibition or ARH-targeted deletion of PTP1B restores the suppression of HGP in obese mice. Additionally, mice that lack PTP1B in AgRP neurons exhibit enhanced ARH insulin signaling and have improved glucose tolerance and insulin sensitivity. Overall, our findings indicate that obesity-induced increases in PTP1B diminish insulin action in the hypothalamus, resulting in unconstrained HGP and contributing to hyperglycemia in obesity.
胰岛素在脑下垂体中的作用可抑制肝葡萄糖生成（HGP）。肥胖通常与对胰岛素的反应减弱有关，导致肥胖小鼠 HGP 的抑制受损。在这里，我们证明阻断饮食诱导肥胖（DIO）小鼠的中枢瘦素信号可恢复肝脏抑制葡萄糖生成的能力。瘦素增加了胰岛素受体磷酸酶 PTP1B 的表达，而 PTP1B 在 DIO 小鼠的脑下垂体中高度表达。我们证明中枢药理学抑制或 ARH 靶向敲除 PTP1B 可恢复肥胖小鼠对 HGP 的抑制。此外，缺乏 AgRP 神经元中 PTP1B 的小鼠表现出增强的 ARH 胰岛素信号传导，并改善葡萄糖耐量和胰岛素敏感性。总的来说，我们的研究结果表明，肥胖诱导的 PTP1B 增加会减弱脑下垂体中的胰岛素作用，导致 HGP 不受限制，并导致肥胖中的高血糖。
