Institute of Medical Physiology, University of Belgrade, Belgrade, Serbia.
Neuroendocrinology. 2012;96(1):24-31. doi: 10.1159/000333963. Epub 2012 Feb 14.
BACKGROUND/AIMS: The antihyperglycaemic drug metformin reduces food consumption through mechanisms that are not fully elucidated. The present study investigated the effects of intracerebroventricular administration of metformin on food intake and hypothalamic appetite-regulating signalling pathways induced by the orexigenic peptide ghrelin.
Rats were injected intracerebroventricularly with ghrelin (5 µg), metformin (50, 100 or 200 µg), 5-amino-imidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR, 25 µg) and L-leucine (1 µg) in different combinations. Food intake was monitored during the next 4 h. Hypothalamic activation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC), regulatory-associated protein of mTOR (Raptor), mammalian target of rapamycin (mTOR) and p70 S6 kinase 1 (S6K) after 1 h of treatment was analysed by immunoblotting.
Metformin suppressed the increase in food consumption induced by intracerebroventricular ghrelin in a dose-dependent manner. Ghrelin increased phosphorylation of hypothalamic AMPK and its targets ACC and Raptor, which was associated with the reduced phosphorylation of mTOR. The mTOR substrate, S6K, was activated by intracerebroventricular ghrelin despite the inhibition of mTOR. Metformin treatment blocked ghrelin-induced activation of hypothalamic AMPK/ACC/Raptor and restored mTOR activity without affecting S6K phosphorylation. Metformin also reduced food consumption induced by the AMPK activator AICAR while the ghrelin-triggered food intake was inhibited by the mTOR activator L-leucine.
Metformin could reduce food intake by preventing ghrelin-induced AMPK signalling and mTOR inhibition in the hypotalamus.
背景/目的：抗高血糖药物二甲双胍通过尚未完全阐明的机制减少食物摄入。本研究探讨了脑室内给予二甲双胍对食欲肽 ghrelin 诱导的食物摄入和下丘脑食欲调节信号通路的影响。
将 ghrelin（5 µg）、二甲双胍（50、100 或 200 µg）、5-氨基咪唑-4-甲酰胺 1-β-D-核糖呋喃苷（AICAR，25 µg）和 L-亮氨酸（1 µg）以不同组合脑室内注射到大鼠体内。在接下来的 4 小时内监测食物摄入量。治疗 1 小时后，通过免疫印迹分析下丘脑 AMP 激活蛋白激酶（AMPK）、乙酰辅酶 A 羧化酶（ACC）、雷帕霉素复合物 1 相关蛋白（Raptor）、哺乳动物雷帕霉素靶蛋白（mTOR）和 p70 S6 激酶 1（S6K）的激活情况。
二甲双胍以剂量依赖的方式抑制脑室内 ghrelin 诱导的食物摄入量增加。Ghrelin 增加了下丘脑 AMPK 及其靶标 ACC 和 Raptor 的磷酸化，这与 mTOR 的磷酸化减少有关。尽管抑制了 mTOR，但脑室内 ghrelin 激活了 mTOR 底物 S6K。二甲双胍处理阻断了 ghrelin 诱导的下丘脑 AMPK/ACC/Raptor 激活，并恢复了 mTOR 活性，而不影响 S6K 磷酸化。二甲双胍还降低了 AMPK 激活剂 AICAR 诱导的食物摄入，而 mTOR 激活剂 L-亮氨酸抑制了 ghrelin 触发的食物摄入。
二甲双胍可通过防止 ghrelin 诱导的下丘脑 AMPK 信号和 mTOR 抑制来减少食物摄入。
