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

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.

• Authors: Eun Roh, Jae Woo Park, Gil Myoung Kang, Chan Hee Lee, Hong Dugu, So Young Gil, Do Kyeong Song, Hyo Jin Kim, Gi Hoon Son, Rina Yu, Min-Seon Kim
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 88 Pg. 51-60 (11 2018) ISSN: 1532-8600 [Electronic] United States
• PMID: 30179604 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Agouti-Related Protein
• Agrp protein, mouse
• Connexin 43
• Neuropeptide Y
• NAD
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Agouti-Related Protein (genetics)
• Animals
• Biological Transport
• Connexin 43 (metabolism)
• Energy Metabolism (drug effects)
• Hyperphagia (prevention & control)
• Hypothalamus (cytology, drug effects, metabolism)
• Injections, Intraperitoneal
• Injections, Intraventricular
• Male
• Mice, Inbred C57BL
• NAD (administration & dosage, pharmacology)
• Neurons (metabolism)
• Neuropeptide Y (genetics)
• Sirtuin 1 (metabolism)
• Transcription, Genetic (drug effects)
• Weight Gain (drug effects)