Adipose tissue NAD+ biology in obesity and insulin resistance: From mechanism to therapy

Nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD+ biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT‐mediated NAD+ biosynthesis, together with its key downstream mediator, namely the NAD+‐dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue‐dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT‐mediated NAD+ biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD+ biology. Obesity‐associated insulin resistance is an important risk factor for type 2 diabetes and cardiovascular disease. Emerging evidence suggests that impairment of adipose tissue NAMPT‐NAD+‐SIRT1 axis leads to the development of insulin resistance in multiple metabolic organs. These findings have provided important mechanistic and clinical insights into obesity and insulin resistance.