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.

中文翻译：

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空腹和生长素释放肽诱导的食物摄取受到下丘脑中NAMPT的调节。

目的下丘脑弓状核中的神经元参与食物摄入和能量消耗的调节，而这些神经元中信号传导的失调促进了肥胖的发展。限速酶在NAD +补救途径烟酰胺磷酸核糖基转移酶（NAMPT）在调节下丘脑能量稳态方面的作用尚未得到广泛研究。方法我们确定小鼠下丘脑中的Nampt mRNA或蛋白水平是否受到饮食诱导的肥胖，禁食和重新喂养以及瘦素和生长素释放肽治疗的影响。用NAMPT的选择性抑制剂FK866或携带针对Nampt的shRNA的rAAV治疗原发性下丘脑神经元，并评估活性氧（ROS）和线粒体呼吸的水平。在脑室内（ICV）介导的FK866给药后，在代谢笼中的小鼠中测量了禁食和生长素释放肽诱导的食物摄入。结果通过施用生长素释放肽和瘦素，下丘脑中的NAMPT水平升高。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。抑制下丘脑神经元的NAMPT会显着降低NAD +的水平，增加ROS的水平，并影响Agrp，Pomc的表达以及与线粒体功能相关的基因。最后，FK866抑制ICV诱导的NAMPT不会引起不适或快感不足，但可以完全消除空腹和饥饿素引起的食物摄入增加。