AIMS: NAD+ deficiency underlies obesity-induced metabolic disturbances. This study evaluated dihydronicotinamide riboside (NRH), a potent NAD+ enhancer, in lean and obese mice and explored whether NRH operates through a unique mechanism involving adenosine kinase (ADK), an enzyme critical for NRH-driven NAD+ synthesis.

METHODS: Pharmacokinetic and pharmacodynamic analyses were performed following a single 250 mg/kg intraperitoneal injection of NRH in healthy mice. In long-term studies, lean and high-fat diet-induced obese mice were treated with 250 mg/kg NRH thrice weekly for 7 weeks. Blood NAD+ levels, body composition, energy expenditure, and glucose and lipid metabolism were monitored. To test ADK's role, the ADK inhibitor ABT702 was co-administered with NRH in obese mice.

RESULTS: NRH entered tissues unassisted and was rapidly metabolized for NAD+ biosynthesis, while ADK inhibition blocked its phosphorylation, leading to NRH accumulation in all examined tissues and possible release back into circulation. The 7-week NRH administration was well-tolerated in both lean and obese mice. In obese mice, NRH improved glucose homeostasis by boosting insulin secretion, enhancing muscle insulin signaling, and reducing hepatic gluconeogenesis. It also lowered fat mass, decreased serum lipids, and improved white adipose function. These benefits were linked to elevated tissue NAD+ levels, enhanced Sirtuin activities, and increased mitochondrial antioxidant defenses. ADK inhibition abolished these effects, confirming that NRH's direct entry into tissues and subsequent phosphorylation is essential for its full benefits.

CONCLUSION: This study establishes NRH as a promising therapeutic agent for obesity-induced metabolic dysfunction, correcting glucose intolerance and hyperlipidemia through ADK-dependent NAD+ enhancement.