NAD 치료의 항비만 효과의 효과의 시상하부 기전 연구

Abstract

Nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1 is an important regulator of hypothalamic neuronal function. Thus, adequate hypothalamic nicotinamide adenine dinucleotide (NAD) content has been reported to be critical for maintaining normal energy homeostasis and circadian rhythm. In mammalian cells, NAD is largely recycled via nicotinamide and nicotinamide mononucleotide (NMN). Previous studies have shown that supplementation with NMN improves obesity/ageing-related metabolic complications in rodents. I investigated whether exogenous NAD increases hypothalamic neuron NAD levels and affects energy metabolism. I also explored mechanisms mediating central metabolic effects of NAD supplement. I found that extracellular NAD was imported into N1 hypothalamic neuronal cells in a connexin 43-dependent manner. Exogenous NAD effectively suppressed NPY and AgRP transcriptional activity, and this effect was mediated by SIRT1 and FOXO1. In mice, central and peripheral NAD administration suppressed fasting-induced hyperphagia and weight gain. Consistent with the in vitro data, inhibition of hypothalamic connexin 43 blocked hypothalamic neuronal NAD uptake as well as NAD-induced anorexia and weight reduction. Diet-induced obese mice had lower hypothalamic NAD content compared to lean mice. Chronic NAD supplement in obese mice rescued hypothalamic NAD deficit and corrected blunted circadian rhythms in feeding, locomotor activity, and energy expenditure. These findings indicate that NAD supplementation is a potential therapeutic method for metabolic disorders accompanied by hypothalamic NAD depletion.