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

Abstract

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.

Keywords: NAD+; NAMPT; PPARγ; SIRT1; adipose tissue; insulin resistance; obesity.

Figure 1. Mammalian NAD⁺ biosynthetic pathways

NAD⁺ biosynthesis is mediated by multiple enzymatic reactions. In mammals, nicotinamide phosphoribosyltransferase (NAMPT) functions as the rate-limiting enzyme in mammalian NAD⁺ biosynthetic pathway from the point of nicotinamide. NAMPT-mediated NAD⁺ biosynthesis critically regulates metabolic function through key NAD⁺-consuming enzymes, such as poly ADP ribose polymerases (PARPs), sirtuins, and CD38, in a tissue-dependent manner. See the text for the details and references. Abbreviations: NMNAT, nicotinamide/nicotinic acid mononucleotide adenylyltransferase; NRK, nicotinamide riboside kinase; NAPRT, nicotinic acid phosphoribosyltransferase; NADS, NAD⁺ synthase; PRPP; 5-phosphoribosyl 1-pyrophosphate.

Figure 2. Impaired NAMPT-mediated NAD⁺ biosynthesis in adipocytes causes insulin resistance in liver and skeletal muscle

Obesity is known to decrease adipose tissue NAMPT expression and NAD⁺ contents in rodents and humans. Reduction of NAMPT-mediated NAD⁺ biosynthesis in adipocytes severely impairs insulin action in liver and skeletal muscle by decreasing adiponectin and increasing free fatty acids (FFA) production [14].

Figure 3. SIRT1 deacetylates and regulates key metabolic regulators in adipocytes

SIRT1 is a NAD⁺-dependent protein deacetylase that regulates many biological processes. In adipocytes, SIRT1 deacetylates lysine residues on key metabolic regulators, including the forkhead transcriptional factor (Foxo1), nuclear factor kappa B (NF-κB), cyclic AMP response element binding protein (CREB), c-Myc, and PPARγ. SIRT1-mediated lysine deacetylation of these proteins affects key metabolic functions in adipocytes. See the text for the details and references.