Fasting- and ghrelin-induced food intake is regulated by NAMPT in the hypothalamus
Fasting- and ghrelin-induced food intake is regulated by NAMPT in the hypothalamus
复制标题
禁食和生长素释放肽诱导的食物摄入由下丘脑中的 NAMPT 调节
DOI：
10.1111/apha.13437
复制
发表时间：
2020-01-14
影响因子：
6.3
通讯作者：
Treebak, Jonas T.
中科院分区：
文献类型：
--
作者：
de Guia, Roldan M.;Hassing, Anna S.;Treebak, Jonas T.
目的下丘脑弓状核神经元参与食物摄入和能量消耗的调节，而这些神经元信号失调会促进肥胖的发生。在NAD（+）回收途径中，限速酶烟酰胺磷酸核糖基转移酶（NAMPT）在调节下丘脑能量稳态中的作用尚未得到广泛研究。方法测定小鼠下丘脑中Nampt mRNA或蛋白水平是否受到饮食性肥胖、禁食和再喂养以及瘦素和胃饥饿素治疗的影响。用选择性NAMPT抑制剂FK866或携带针对NAMPT的shRNA的rAAV处理初级下丘脑神经元，并评估活性氧（ROS）和线粒体呼吸水平。在脑室内（ICV）介导的FK866给药后，在代谢笼中测量小鼠的空腹和胃饥饿素诱导的食物摄入量。结果下丘脑NAMPT水平在胃促生长素和瘦素的作用下升高。在饮食诱导的肥胖小鼠中，下丘脑中NAMPT的蛋白质和mRNA水平均下降。NAMPT抑制下丘脑初级神经元显著降低NAD（+）水平，增加ROS水平，影响Agrp、Pomc和线粒体功能相关基因的表达。最后，FK866诱导的icv诱导的NAMPT抑制没有引起不适或快感缺乏，但完全消除了禁食和胃饥饿素诱导的食物摄入增加。结论下丘脑神经元中NAMPT水平的调节对控制空腹和胃饥饿素诱导的食物摄入具有重要意义。
Aim Neurons in the arcuate nucleus of the hypothalamus are involved in regulation of food intake and energy expenditure, and dysregulation of signalling in these neurons promotes development of obesity. The role of the rate-limiting enzyme in the NAD(+) salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), for regulation energy homeostasis by the hypothalamus has not been extensively studied. Methods We determined whether Nampt mRNA or protein levels in the hypothalamus of mice were affected by diet-induced obesity, by fasting and re-feeding, and by leptin and ghrelin treatment. Primary hypothalamic neurons were treated with FK866, a selective inhibitor of NAMPT, or rAAV carrying shRNA directed against Nampt, and levels of reactive oxygen species (ROS) and mitochondrial respiration were assessed. Fasting and ghrelin-induced food intake was measured in mice in metabolic cages after intracerebroventricular (ICV)-mediated FK866 administration. Results NAMPT levels in the hypothalamus were elevated by administration of ghrelin and leptin. In diet-induced obese mice, both protein and mRNA levels of NAMPT decreased in the hypothalamus. NAMPT inhibition in primary hypothalamic neurons significantly reduced levels of NAD(+), increased levels of ROS, and affected the expression of Agrp, Pomc and genes related to mitochondrial function. Finally, ICV-induced NAMPT inhibition by FK866 did not cause malaise or anhedonia, but completely ablated fasting- and ghrelin-induced increases in food intake. Conclusion Our findings indicate that regulation of NAMPT levels in hypothalamic neurons is important for the control of fasting- and ghrelin-induced food intake.