NRH, a potent NAD+ booster, improves glucose homeostasis and lipid metabolism in diet-induced obese mice though an active adenosine kinase pathway

Abstract

NAD⁺ deficiency underlies obesity-induced metabolic disturbances. Here we evaluated the treatment effect of a new and potent NAD⁺ enhancer, dihydronicotinamide riboside (NRH), in diet-induced obese mice with hyperglycemia and hyperlipidemia. Administering NRH for 7 weeks improved glucose homeostasis by enhancing pancreatic beta-cell functional mass, increasing muscle insulin sensitivity, and reducing hepatic gluconeogenesis. NRH treatment also mobilized fat deposition, reduced circulating lipid, and improved white adipose function. Significant elevation in multi-tissue NAD⁺ levels and sirtuin (SIRT) activities, especially SIRT3, mediated these metabolic improvements. Inhibiting adenosine kinase (ADK), a newly recognized enzyme in the NRH-induced NAD⁺ synthesis pathway, blocked NRH’s effect in improving glucose and lipid metabolism. ADK inhibition also reduced tissue NAD⁺ elevation and the subsequent activation of SIRT3, suggesting an active ADK pathway is necessary for NRH-induced metabolic benefits. These observations, for the first time, establish NRH as a promising intervention for correcting obesity-induced metabolic syndrome.