Department of Physiology, School of Medicine--Instituto de Investigaciones Sanitarias (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain.
Diabetes. 2011 Apr;60(4):1177-85. doi: 10.2337/db10-0802. Epub 2011 Mar 8.
Ghrelin is a stomach-derived peptide that increases food intake through the activation of hypothalamic AMP-activated protein kinase (AMPK). However, the molecular mechanisms initiated by the activation of the ghrelin receptor, which in turn lead to AMPK activation, remain unclear. Sirtuin 1 (SIRT1) is a deacetylase activated in response to calorie restriction that acts through the tumor suppressor gene p53. We tested the hypothesis that the central SIRT1/p53 pathway might be mediating the orexigenic action of ghrelin.
SIRT1 inhibitors, such as Ex527 and sirtinol, and AMPK activators, such as AICAR, were administered alongside ghrelin in the brain of rats and mice (wild-type versus p53 knockout [KO]). Their hypothalamic effects on lipid metabolism and changes in transcription factors and neuropeptides were assessed by Western blot and in situ hybridization.
The central pretreatment with Ex527, a potent SIRT1 inhibitor, blunted the ghrelin-induced food intake in rats. Mice lacking p53, a target of SIRT1 action, failed to respond to ghrelin in feeding behavior. Ghrelin failed to phosphorylate hypothalamic AMPK when rats were pretreated with Ex527, as it did in p53 KO mice. It is noteworthy that the hypothalamic SIRT1/p53 pathway seems to be specific for mediating the orexigenic action of ghrelin, because central administration of AICAR, a potent AMPK activator, increased food intake in p53 KO mice. Finally, blockade of the central SIRT1 pathway did not modify ghrelin-induced growth hormone secretion.
Ghrelin specifically triggers a central SIRT1/p53 pathway that is essential for its orexigenic action, but not for the release of growth hormone.
Ghrelin 是一种源自胃的肽，通过激活下丘脑 AMP 激活的蛋白激酶（AMPK）增加食物摄入。然而，ghrelin 受体激活引发的分子机制，进而导致 AMPK 激活，目前仍不清楚。Sirtuin 1（SIRT1）是一种响应热量限制而激活的去乙酰化酶，通过肿瘤抑制基因 p53 发挥作用。我们检验了这样一个假设，即中央 SIRT1/p53 途径可能介导了 ghrelin 的食欲作用。
在大鼠和小鼠（野生型与 p53 敲除 [KO]）的大脑中，同时给予 SIRT1 抑制剂（如 Ex527 和 sirtinol）和 AMPK 激活剂（如 AICAR）与 ghrelin 一起给药，评估其对脂代谢的下丘脑影响，以及转录因子和神经肽的变化。通过 Western blot 和原位杂交进行检测。
中央预处理用 Ex527，一种有效的 SIRT1 抑制剂，可减弱大鼠中 ghrelin 诱导的摄食。缺乏 SIRT1 作用靶点 p53 的小鼠在摄食行为中对 ghrelin 无反应。当大鼠用 Ex527 预处理时，ghrelin 未能磷酸化下丘脑 AMPK，就像在 p53 KO 小鼠中一样。值得注意的是，下丘脑 SIRT1/p53 途径似乎是专门介导 ghrelin 的食欲作用的，因为中央给予 AICAR，一种有效的 AMPK 激活剂，增加了 p53 KO 小鼠的食物摄入。最后，阻断中央 SIRT1 途径不会改变 ghrelin 诱导的生长激素分泌。
Ghrelin 特异性触发中央 SIRT1/p53 途径，这对于其食欲作用是必需的，但对于生长激素的释放不是必需的。
