Abstract
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.
Conclusions
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.
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Introduction
Nicotinamide adenine dinucleotide (NAD) regulates the cellular redox state by mediating hydride transfer in oxidoreductive metabolic processes [1]. Moreover, NAD is a pivotal cosubstrate in numerous biochemical reactions catalyzed by NAD-dependent deacetylases known as sirtuins, poly[adenosine diphosphate (ADP)-ribose] polymerase (PARP), and cyclic ADP-ribose cyclase/cluster of differentiation 38 (CD38) [2,3]. In mammals, most cellular NAD is synthesized via a recycling pathway wherein nicotinamide is converted to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (Nampt) and then to NAD by nicotinamide mononucleotide adenylyltransferase (Nmnat) [2,3]. NAD can also be synthesized de novo from tryptophan or nicotinamide ribose (NR), a trace nutrient [2,3].
Sirtuins play important roles in cellular adaptive responses to stresses such as fasting, DNA damage, and oxidative stress [4]. SIRT1, a prototype sirtuin, is the mammalian orthologue of Sir2 which mediates caloric restriction-induced longevity in yeasts [5]. In peripheral metabolic organs, SIRT1 regulates cellular metabolism by deacetylating key transcriptional regulators including peroxisome proliferator-activated receptor-γ (PPARγ), PPARγ coactivator-1α, and forkhead transcription factor FOXOs [6, 7, 8].
Recent studies reported a critical role for SIRT1 in the hypothalamic regulation of energy homeostasis and circadian physiology [9, 10, 11, 12, 13, 14]. SIRT1 in hypothalamic proopiomelanocortin (POMC) neurons and steroidogenic factor 1 (SF1) neurons counters diet-induced obesity [11,14]. SIRT1 in orexigenic neuropeptide Y (NPY)/Agouti-related protein (AgRP) neurons is an important determinant of neuronal excitability and the response to ghrelin [12]. Furthermore, SIRT1 in master clock neurons of the suprachiasmatic nucleus critically regulate expression of clock genes [15,16]. Notably, SIRT1 expression in the hypothalamic arcuate nucleus (ARC) and suprachiasmatic nucleus decreases with aging [15,17]; this phenomenon has been suggested as the central mechanism underlying age-associated weight gain and decline in circadian function [15,17]. In addition to aging, chronic high-fat, high-sucrose food consumption also reduces hypothalamic SIRT1 protein levels and NAD content in mice, leading to decreased SIRT1 activity in hypothalamic neurons [17].
Because of the importance of NAD-dependent SIRT1 activity in normal metabolic function [18], therapeutic strategies activating the cellular NAD-SIRT1 axis have been proposed. Several studies have reported the metabolic benefits of SIRT1-activating compounds including polyphenols such as resveratrol and synthetic small molecule SIRT1 activators [19, 20, 21, 22]. The limitation of this strategy is that SIRT1 activity depends on the cellular NAD content. Therefore, researchers have attempted to increase NAD levels in metabolic organs by supplying NAD precursors [23, 24, 25]; supplementation with the NAD precursors NMN and NR reportedly exerted beneficial metabolic effects in obese or aged mice by restoring NAD levels in peripheral metabolic organs.
Interestingly, extracellular NAD treatment can increase cellular NAD levels and rescue cells from NAD depletion-induced death in cultured cells [26]. Therefore, we investigated the effect of exogenous NAD on the hypothalamic NAD content and attempted to identify the molecular mechanism underlying hypothalamic NAD uptake. We also examined the effects of centrally and peripherally administered NAD on energy metabolism in mice.
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