Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice via Extracellular Vesicles

Nicotinamide phosphoribosyltransferase (NAMPT) maintains the cellular NAD⁺ pool, and diminished adipocyte NAMPT activity has been implicated in aging-and obesity-related metabolic dysfunction. We generated adipocyte-specific NAMPT overexpressing (ANOV) mice and examined their metabolic phenotypes. Male ANOV mice were protected from high-fat diet–induced metabolic dysfunction, including the development of adipose tissue inflammation and glucose intolerance. In contrast, female ANOV mice were less protected from metabolic dysfunction, possibly due to higher endogenous expression of NAMPT in wild-type female mice. Livers of ANOV mice showed improved insulin signaling, increased NAD⁺ content, and reduced steatosis, suggesting that NAMPT regulates inter-organ communication between adipocytes and hepato-cytes. We show that adipose tissue–derived extracellular vesicles (EVs) isolated from ANOV mice enhanced insulin signaling in HepG2 cells and liver and improved glucose tolerance in mice. NAMPT overexpression altered EV cargo composition, including decreased ceramides and increased content of NAD⁺ and NAMPT. Treating HepG2 cells with an NAMPT inhibitor blunted the effects of ANOV-EV on insulin signaling, suggesting that transfer of NAMPT to recipient cells mediates at least some of the beneficial effects of ANOV-EV. Collectively, these data highlight a novel mechanism by which adipocyte NAMPT regulates systemic metabolic dysfunction via EVs.