Toronto General Research Institute, University Health Network, Toronto, Canada ; Departments of Physiology, University of Toronto, Toronto, Canada.
Toronto General Research Institute, University Health Network, Toronto, Canada ; Departments of Medicine, University of Toronto, Toronto, Canada.
Mol Metab. 2013 Nov 28;3(2):202-8. doi: 10.1016/j.molmet.2013.11.007. eCollection 2014 Apr.
Insulin, leptin and GLP-1 signal in the mediobasal hypothalamus (MBH) to lower hepatic glucose production (GP). MBH glucagon action also inhibits GP but the downstream signaling mediators remain largely unknown. In parallel, a lipid-sensing pathway involving MBH AMPK→malonyl-CoA→CPT-1→LCFA-CoA→PKC-δ leading to the activation of KATP channels lowers GP. Given that glucagon signals through the MBH PKA to lower GP, and PKA inhibits AMPK in hypothalamic cell lines, a possibility arises that MBH glucagon-PKA inhibits AMPK, elevates LCFA-CoA levels to activate PKC-δ, and activates KATP channels to lower GP. We here report that neither molecular or chemical activation of MBH AMPK nor inhibition of PKC-δ negated the effect of MBH glucagon. In contrast, molecular and chemical inhibition of MBH KATP channels negated MBH glucagon's effect to lower GP. Thus, MBH glucagon signals through a lipid-sensing independent but KATP channel-dependent pathway to regulate GP.
胰岛素、瘦素和 GLP-1 信号在中脑基底部（MBH）降低肝葡萄糖生成（GP）。MBH 胰高血糖素作用也抑制 GP，但下游信号转导介质在很大程度上仍然未知。与此同时，涉及 MBH AMPK→丙二酰辅酶 A→CPT-1→LCFA-CoA→PKC-δ 的脂质感应途径导致 KATP 通道激活，从而降低 GP。鉴于胰高血糖素通过 MBH PKA 信号传递以降低 GP，并且 PKA 在下丘脑细胞系中抑制 AMPK，因此出现了一种可能性，即 MBH 胰高血糖素-PKA 抑制 AMPK，升高 LCFA-CoA 水平以激活 PKC-δ，并激活 KATP 通道以降低 GP。我们在这里报告说，MBH AMPK 的分子或化学激活或 PKC-δ 的抑制都没有消除 MBH 胰高血糖素的作用。相比之下，MBH KATP 通道的分子和化学抑制消除了 MBH 胰高血糖素降低 GP 的作用。因此，MBH 胰高血糖素通过一种不依赖于脂质感应但依赖于 KATP 通道的途径传递信号来调节 GP。
