The importance of adipose tissue NAD+ biology in regulating metabolic flexibility.

Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme regulating cellular energy metabolism across all species. Recent studies have shown the pleiotropic roles of adipose tissue NAD+ biology in adipose tissue and whole-body metabolism. The major purpose of the present study was to test the hypothesis that adipose tissue NAD+ biosynthesis, mediated by nicotinamide phosphoribosyltransferase (NAMPT), is a physiological regulator of whole-body metabolic flexibility. To this end, we analyzed adipocyte-specific Nampt knockout (ANKO) mice and subcutaneous white adipose tissue (WAT) biopsy samples obtained from human subjects. We found ANKO mice preferably utilized glucose substrate during the light period or after prolonged fasting. In contrast, ANKO mice had marked decreases in stimulation of glucose oxidation and suppression of fat oxidation during the postprandial status despite hyperinsulinemia. Data obtained from RNA-sequencing of WAT suggest that loss of NAMPT causes inflammation, oxidative stress, defective fatty acid oxidation, and mitochondrial dysfunction in WAT, key features of obesity and metabolic inflexibility. We also found WAT NAD+ concentration was decreased in people with obesity and insulin resistance compared with those who were non-obese and insulin-sensitive. In addition, bariatric surgery-induced 20% weight loss increased WAT NAD+ concentration in people with obesity. Taken together, our results reveal the importance of adipose tissue NAMPT-mediated NAD+ biosynthesis in regulating whole-body metabolic flexibility. Our results also provide translational and clinical insight into adipose tissue NAD+ biology in obesity and whole-body metabolic health. We determined the effects of adipocyte-specific Nampt deletion on subcutaneous white adipose tissue gene expression profiling by analyzing control (flox/flox) and adipocyte-specific Nampt knockout (ANKO) mice (n=3 per group).