Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition
Gut-derived GIP activates central Rap1 to impair neural leptin sensitivity during overnutrition
复制标题
DOI：
10.1172/jci126107
复制
发表时间：
2019-09-03
影响因子：
15.9
通讯作者：
Fukuda, Makoto
中科院分区：
文献类型：
--
作者：
Kaneko, Kentaro;Fu, Yukiko;Fukuda, Makoto
营养过剩是肥胖的主要驱动因素，它会降低下丘脑对外源性瘦素的反应，瘦素是能量平衡的关键激素。在这里，我们的目标是确定一种生理信号，该信号源于热量摄入过多，并对下丘脑瘦素的作用起到负面控制作用。我们发现，胃抑制多肽受体(GIPR)缺乏肠源性胰岛素激素GIP对饮食诱导的神经性瘦素抵抗具有保护作用。此外，一种中和GIPR的中央注射抗体在饮食诱导的肥胖小鼠中具有显著的减肥效果，包括减轻体重和肥胖，以及降低下丘脑SOCS3的水平，SOCS3是瘦素作用的抑制剂。相比之下，中央注射GIP降低了下丘脑对瘦素的敏感性，并增加了下丘脑SOCS3的水平。最后，我们发现GIP增加了脑中小GTP酶Rap1的活性形式，并且它的激活是GIP的中枢作用所必需的。总之，我们的结果确认大脑中的GIPR/Rap1信号是一条将营养过剩与神经瘦素活动控制联系起来的分子途径。
Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.