Department of Biomedical Science, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; Appetite Regulation Laboratory, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
Appetite Regulation Laboratory, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
Metabolism. 2018 Nov;88:51-60. doi: 10.1016/j.metabol.2018.08.005. Epub 2018 Sep 1.
Nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1 is an important regulator of hypothalamic neuronal function. Thus, an adequate hypothalamic NAD content is critical for maintaining normal energy homeostasis.
We investigated whether NAD supplementation increases hypothalamic NAD levels and affects energy metabolism in mice. Furthermore, we investigated the mechanisms underlying the effects of exogenous NAD on central metabolism upon entering the hypothalamus.
Central and peripheral NAD administration suppressed fasting-induced hyperphagia and weight gain in mice. Extracellular NAD was imported into N1 hypothalamic neuronal cells in a connexin 43-dependent and CD73-independent manner. Consistent with the in vitro data, inhibition of hypothalamic connexin 43 blocked hypothalamic NAD uptake and NAD-induced anorexia. Exogenous NAD suppressed NPY and AgRP transcriptional activity, which was mediated by SIRT1 and FOXO1.
Exogenous NAD is effectively transported to the hypothalamus via a connexin 43-dependent mechanism and increases hypothalamic NAD content. Therefore, NAD supplementation is a potential therapeutic method for metabolic disorders characterized by hypothalamic NAD depletion.
烟酰胺腺嘌呤二核苷酸（NAD）依赖性去乙酰化酶 SIRT1 是下丘脑神经元功能的重要调节剂。因此，足够的下丘脑 NAD 含量对于维持正常的能量平衡至关重要。
我们研究了 NAD 补充是否会增加下丘脑 NAD 水平并影响小鼠的能量代谢。此外，我们研究了外源性 NAD 进入下丘脑后对中枢代谢的影响的机制。
中枢和外周 NAD 给药可抑制小鼠禁食诱导的过度进食和体重增加。细胞外 NAD 以连接蛋白 43 依赖性和 CD73 非依赖性的方式被导入 N1 下丘脑神经元细胞。与体外数据一致，抑制下丘脑连接蛋白 43 可阻断下丘脑 NAD 的摄取和 NAD 诱导的厌食症。外源性 NAD 抑制 NPY 和 AgRP 的转录活性，这是由 SIRT1 和 FOXO1 介导的。
外源性 NAD 通过连接蛋白 43 依赖性机制有效地转运到下丘脑，并增加下丘脑 NAD 含量。因此，NAD 补充可能是治疗以下丘脑 NAD 耗竭为特征的代谢紊乱的潜在方法。
