Adipocyte-specific inactivation of NAMPT, a key NAD⁺ biosynthetic enzyme, causes a metabolically unhealthy lean phenotype in female mice during aging

Nicotinamide adenine dinucleotide (NAD⁺) is a universal coenzyme regulating cellular energy metabolism in many cell types. Recent studies have demonstrated the close relationships between defective NAD⁺ metabolism and aging and age-associated metabolic diseases. The major purpose of the present study was to test the hypothesis that NAD⁺ biosynthesis, mediated by a rate-limiting NAD⁺ biosynthetic enzyme, nicotinamide phosphoribosyltransferase (NAMPT), is essential for maintaining normal adipose tissue function and whole body metabolic health during the aging process. To this end, we provided in-depth and comprehensive metabolic assessments for female adipocyte-specific Nampt knockout (ANKO) mice during aging. We first evaluated body fat mass in young (≤4-mo-old), middle aged (10-14-mo-old), and old (≥18-mo-old) mice. Intriguingly, adipocyte-specific Nampt deletion protected against age-induced obesity without changing energy balance. However, data obtained from the hyperinsulinemic-euglycemic clamp procedure (HECP) demonstrated that, despite the lean phenotype, old ANKO mice had severe insulin resistance in skeletal muscle, heart, and white adipose tissue (WAT). Old ANKO mice also exhibited hyperinsulinemia and hypoadiponectinemia. Mechanistically, loss of Nampt caused marked decreases in WAT gene expression of lipogenic targets of peroxisome proliferator-activated receptor gamma (PPAR-γ) in an age-dependent manner. In addition, administration of a PPAR-γ agonist rosiglitazone restored fat mass and improved metabolic abnormalities in old ANKO mice. In conclusion, these findings highlight the importance of the NAMPT-NAD⁺-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue, and whole body metabolic function in female mice during aging.NEW & NOTEWORTHY Defective NAD⁺ metabolism is associated with aging and age-associated metabolic diseases. In the present study, we provided in-depth metabolic assessments in female mice with adipocyte-specific inactivation of a key NAD⁺ biosynthetic enzyme NAMPT and revealed an unexpected role of adipose tissue NAMPT-NAD⁺-PPAR-γ axis in maintaining functional integrity and quantity of adipose tissue and whole body metabolic health during the aging process.