Integrative Metabolism and Environmental Influences, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
FASEB J. 2021 May;35(5):e21450. doi: 10.1096/fj.202002740R.
Agouti-related protein (AgRP) neurons in the arcuate nucleus of the hypothalamus regulates food intake and whole-body metabolism. NAD regulates multiple cellular processes controlling energy metabolism. Yet, its role in hypothalamic AgRP neurons to control food intake is poorly understood. Here, we aimed to assess whether genetic deletion of nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme in NAD production, affects AgRP neuronal function to impact whole-body metabolism and food intake. Metabolic parameters during fed and fasted states, and upon systemic ghrelin and leptin administration were studied in AgRP-specific Nampt knockout (ARNKO) mice. We monitored neuropeptide expression levels and density of AgRP neurons in ARNKO mice from embryonic to adult age. NPY cells were used to determine effects of NAMPT inhibition on neuronal viability, energy status, and oxidative stress in vitro. In these cells, NAD depletion reduced ATP levels, increased oxidative stress, and promoted cell death. Agrp expression in the hypothalamus of ARNKO mice gradually decreased after weaning due to progressive AgRP neuron degeneration. Adult ARNKO mice had normal glucose and insulin tolerance, but exhibited an elevated respiratory exchange ratio (RER) when fasted. Remarkably, fasting-induced food intake was unaffected in ARNKO mice when evaluated in metabolic cages, but fasting- and ghrelin-induced feeding and body weight gain decreased in ARNKO mice when evaluated outside metabolic cages. Collectively, deletion of Nampt in AgRP neurons causes progressive neurodegeneration and impairs fasting and ghrelin responses in a context-dependent manner. Our data highlight an essential role of Nampt in AgRP neuron function and viability.
弓状核中的 Agouti 相关蛋白 (AgRP) 神经元调节食物摄入和全身代谢。NAD 调节控制能量代谢的多种细胞过程。然而，其在下丘脑 AgRP 神经元中控制食物摄入的作用仍知之甚少。在这里，我们旨在评估烟酰胺磷酸核糖转移酶 (Nampt) 的基因缺失是否会影响 AgRP 神经元的功能，从而影响全身代谢和食物摄入，Nampt 是 NAD 产生的限速酶。在 AgRP 特异性 Nampt 敲除 (ARNKO) 小鼠中研究了进食和禁食状态期间以及系统给予胃饥饿素和瘦素时的代谢参数。我们监测了 ARNKO 小鼠从胚胎到成年期的神经肽表达水平和 AgRP 神经元密度。使用 NPY 细胞来确定 NAMPT 抑制对神经元活力、能量状态和氧化应激的影响。在这些细胞中，NAD 耗竭降低了 ATP 水平，增加了氧化应激，并促进了细胞死亡。由于 AgRP 神经元的进行性退化，ARNKO 小鼠下丘脑的 Agrp 表达在断奶后逐渐降低。成年 ARNKO 小鼠具有正常的葡萄糖和胰岛素耐量，但在禁食时表现出升高的呼吸交换率 (RER)。值得注意的是，当在代谢笼中评估时，ARNKO 小鼠的禁食诱导的食物摄入不受影响，但当在代谢笼外评估时，ARNKO 小鼠的禁食和胃饥饿素诱导的进食和体重增加减少。总之，AgRP 神经元中 Nampt 的缺失会导致进行性神经退行性变，并以依赖于上下文的方式损害禁食和胃饥饿素反应。我们的数据强调了 Nampt 在 AgRP 神经元功能和活力中的重要作用。
