From the Toronto General Hospital Research Institute, University Health Network, Toronto M5G 1L7, Canada.
Departments of Physiology and.
J Biol Chem. 2018 Mar 16;293(11):4159-4166. doi: 10.1074/jbc.RA117.000838. Epub 2018 Jan 26.
The responsiveness of glucose sensing to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake In both rodents and humans, glucose sensing is lost in diabetes and obesity, but the site(s) of impairment remains elusive. Here, we first report that short-term high-fat feeding disrupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat-fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased whole-body glucose tolerance during an intravenous glucose tolerance test. Finally, both chemical inhibition of hypothalamic lactate dehydrogenase (LDH) (achieved via hypothalamic LDH inhibitor oxamate infusion) and molecular knockdown of LDHA (achieved via hypothalamic lentiviral LDHA shRNA injection) negated the ability of hypothalamic leptin infusion to enhance glucose sensing to lower glucose production in high fat-fed rats. In summary, our findings illustrate that leptin enhances LDHA-dependent glucose sensing in the hypothalamus to lower glucose production in high-fat-fed rodents .
葡萄糖感应对调节全身葡萄糖稳态的反应能力取决于葡萄糖升高降低肝葡萄糖生成和增加外周葡萄糖摄取的能力。在啮齿动物和人类中，糖尿病和肥胖症会导致葡萄糖感应丧失，但损害的部位仍不清楚。在这里，我们首先报告短期高脂肪喂养会破坏大鼠下丘脑的葡萄糖感应，从而降低葡萄糖生成。其次，将瘦素注入高脂肪喂养的大鼠的下丘脑，可在胰腺（基础胰岛素）-正常血糖钳夹期间恢复下丘脑的葡萄糖感应，降低葡萄糖生成，并在静脉葡萄糖耐量试验期间增加全身葡萄糖耐量。最后，下丘脑乳酸脱氢酶（LDH）的化学抑制（通过下丘脑 LDH 抑制剂氧代酸盐输注实现）和 LDHA 的分子敲低（通过下丘脑慢病毒 LDHA shRNA 注射实现）都消除了下丘脑瘦素输注增强葡萄糖感应，降低高脂肪喂养大鼠葡萄糖生成的能力。总之，我们的研究结果表明，瘦素增强了下丘脑 LDHA 依赖性葡萄糖感应，以降低高脂肪喂养啮齿动物的葡萄糖生成。
