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Metabolism. 2018 Nov;88:51-60. doi: 10.1016/j.metabol.2018.08.005. Epub 2018 Sep 1.

Exogenous nicotinamide adenine dinucleotide regulates energy metabolism via hypothalamic connexin 43.

Author information

1
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.
2
Appetite Regulation Laboratory, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
3
Appetite Regulation Laboratory, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea; Division of Endocrinology and Metabolism, Asan Medical Center, Seoul 05505, Republic of Korea.
4
Department of Biomedical Science, Korea University College of Medicine, Seoul 02841, Republic of Korea.
5
Department of Food Science and Nutrition, University of Ulsan, Ulsan 44610, Republic of Korea.
6
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; Division of Endocrinology and Metabolism, Asan Medical Center, Seoul 05505, Republic of Korea. Electronic address: mskim@amc.seoul.kr.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

KEYWORDS:

Connexin 43; Energy metabolism; Hypothalamus; NAD; Supplement

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