NAMPT-mediated NAD biosynthesis is indispensable for adipose tissue plasticity and development of obesity

Abstract

ObjectiveThe ability of adipose tissue to expand and contract in response to fluctuations in nutrient availability is essential for the maintenance of whole-body metabolic homeostasis. Given the nutrient scarcity that mammals faced for millions of years, programs involved in this adipose plasticity were likely evolved to be highly efficient in promoting lipid storage. Ironically, this previously advantageous feature may now represent a metabolic liability given the caloric excess of modern society. We speculate that nicotinamide adenine dinucleotide (NAD+) biosynthesis exemplifies this concept. Indeed NAD+/NADH metabolism in fat tissue has been previously linked with obesity, yet whether it plays a causal role in diet-induced adiposity is unknown. Here we investigated how the NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) supports adipose plasticity and the pathological progression to obesity.MethodsWe utilized a newly generated Nampt loss-of-function model to investigate the tissue-specific and systemic metabolic consequences of adipose NAD+ deficiency. Energy expenditure, glycemic control, tissue structure, and gene expression were assessed in the contexts of a high dietary fat burden as well as the transition back to normal chow diet.ResultsFat-specific Nampt knockout (FANKO) mice were completely resistant to high fat diet (HFD)-induced obesity. This was driven in part by reduced food intake. Furthermore, HFD-fed FANKO mice were unable to undergo healthy expansion of adipose tissue mass, and adipose depots were rendered fibrotic with markedly reduced mitochondrial respiratory capacity. Yet, surprisingly, HFD-fed FANKO mice exhibited improved glucose tolerance compared to control littermates. Removing the HFD burden largely reversed adipose fibrosis and dysfunction in FANKO animals whereas the improved glucose tolerance persisted.ConclusionsThese findings indicate that adipose NAMPT plays an essential role in handling dietary lipid to modulate fat tissue plasticity, food intake, and systemic glucose homeostasis.

Monounsaturated Fatty Acids in a High‐Fat Diet and Niacin Protect from White Fat Dysfunction in the Metabolic Syndrome

“…However, chronic ingestion of NAD + precursors during adulthood was previously shown to have little, if any, effect on body weight in wild type mice and even in the adipose‐specific NAMPT knockout mice fed on a chow diet. Only when mice are subjected to a challenge of an HFD, the NAD + salvage pathway then acts to modulate adipose tissue plasticity and metabolic network for development of obesity . The stepwise approach in the current scenario was then the combination of an HFD to trigger the metabolic gate for NAD + biogenesis via the salvage pathway and of niacin to fuel it.…”

“…Niacin is also one of the most efficient agents to improve blood lipid profiles and to inhibit WAT lipolysis . As the rate‐limiting enzyme of the NAD + salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT) was recently reported to play a role in WAT plasticity and the development of obesity . Similar to what is seen with NAMPT, the expression of adipose sirtuins (SIRTs) that use NAD + as their substrate is lower in obese subjects and decreases in mice on HFD .…”

Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

“…Whole-body deletion of Nampt in mice is embryonically lethal, 1 but tissue-specific Nampt knockout/ knockdown models are viable and produce various phenotypes such as enhanced skeletal muscle fibre degeneration and loss of strength in mouse skeletal muscle, 2 impaired neuromuscular junction in projection neurons, 3 retinal dysfunction in rod or cone photoreceptors, 4 reduced regeneration of the liver after partial hepatectomy, 5 and impaired adipose tissue plasticity and organ-specific insulin resistance. 6,7 These studies highlight the importance of NAMPT and the ability to maintain NAD + levels in different tissues. However, the role of NAMPT in the hypothalamus, which is involved in the control of food intake and whole-body metabolism, is still very limited.…”

“…In most mammalian tissues, the majority of NAD + is synthesized from nicotinamide through the salvage pathway controlled by nicotinamide phosphoribosyltransferase (NAMPT, Figure ). Whole‐body deletion of Nampt in mice is embryonically lethal, but tissue‐specific Nampt knockout/knockdown models are viable and produce various phenotypes such as enhanced skeletal muscle fibre degeneration and loss of strength in mouse skeletal muscle, impaired neuromuscular junction in projection neurons, retinal dysfunction in rod or cone photoreceptors, reduced regeneration of the liver after partial hepatectomy, and impaired adipose tissue plasticity and organ‐specific insulin resistance . These studies highlight the importance of NAMPT and the ability to maintain NAD + levels in different tissues.…”

Aerobic and resistance exercise training reverses age‐dependent decline in NAD+salvage capacity in human skeletal muscle

“…To this end, we assessed the age-dependent effect of 12 weeks of either aerobic or resistance exercise training on skeletal muscle abundance of NAD + salvage enzymes (i.e., NAMPT, NRK, and NMNATs). In light of evidence suggesting that the ability to generate NAD + by NAMPT in adipose tissue is important for adipose function (Nielsen et al 2018), and clinical studies showing that acute aerobic exercise induces NAMPT expression in human subcutaneous abdominal adipose tissue (Frydelund-Larsen et al 2007), we also determined whether the abundance of NAD + salvage pathway enzymes are affected by age or HIIT in biopsies of human abdominal subcutaneous adipose tissue.…”