Our bodies have evolved over millions of years to be very efficient at storing energy from excess food as fat deposits, as a key biological survival mechanism for times of food scarcity. Today, when so many of us have an abundance of calorie-rich, high-fat food readily available, the same survival mechanism that is so good at storing fat means that obesity has become a growing global issue.  Studies in mice by scientists at the University of Copenhagen in Denmark have now shown how it is possible to genetically prevent animals from becoming obese, by deleting a single enzyme, called nicotinamide phosphoribosyltransferase (NAMPT), in the animals’ adipose tissues. These knockout mice were found to be completely resistant to becoming overweight, even when fed a high-fat diet (HFD) that contained more than 50% fat.

“We gave the mice a diet that more or less corresponds to continuously eating burgers and pizza,” comments Karen Nørgaard Nielsen, who is a Ph.D. student at the Novo Nordisk Foundation Center for Basic Metabolic Research, and first author on the team’s published paper in Molecular Metabolism. “Still, it was impossible for them to expand their fat tissue.”

The authors aren’t suggesting that blocking NAMPT would be a viable option for treating obesity in humans, as the enzyme plays a central role in NAD+/NADH metabolism. However, they suggest that their findings could help scientists develop more targeted therapeutic approaches. The team reports on its studies in a paper entitled “NAMPT-Mediated NAD+ Biosynthesis Is Indispensable for Adipose Tissue Plasticity and Development of Obesity.”

Adipose tissue displays “remarkable plasticity” that allows it to increase the number and size of fat cells so that it accumulates or releases fat stores in response to food availability and hormone signaling, the authors write. However, when the system is subjected to continual, sustained calorie oveload, energy balance is disrupted, leading to tissue inflammation, insulin resistance, and eventually systemic metabolic dysfunction. “NAMPT in fat tissue was likely once an extraordinary benefit to our ancestors, but in today's society full of high-fat, calorically dense foods, it may now pose a liability,” says Zachary Gerhart-Hines, Ph.D., from the Novo Nordisk Foundation Center for Basic Metabolic Research and corresponding author on the study. 

Interestingly, NAMPT is generally viewed as an enzyme that could be boosted for therapeutic purposes, while NAMPT inhibitors have been investigated for treating different forms of cancer. “'NAMPT appears to increase the metabolic functionality of almost every tissue in the body in which it has been studied,” Dr. Gerhart-Hines continues. “For example, there are indications that the liver and skeletal muscle may benefit from increased NAMPT activity. We similarly find that NAMPT is critical for fat tissue function. Unfortunately, that function is efficiently storing fat.”

Previous studies in mice have shown that adipose NAMPT expression is reduced when animals are fed a HFD and induced when calories are restricted. Studies in humans suggest that visceral NAMPT expression and serum NAMPT levels correlate positively with different measures of obesity, while NAMPT levels in subcutaneous adipose are lower in obese subjects. “These divergent patterns of NAMPT association suggest differing depot-specific NAMPT contributions in human fat and make it difficult to assign a positive or negative role of NAMPT in metabolic syndrome,” the authors write.

To try and find out whether NAMPT may play a causative role in adipose tissue function and the development of obesity, the researchers engineered a strain of mouse that lacked NAMPT specifically in adipose tissue. Initial studies in male fat-specific Nampt knockout (FANKO) mice showed that the animals were “completely resistant to HFD-induced obesity,” even when fed a diet that contained up to 60% fat for weeks on end. In fact, the pattern of weight gain by FANKO mice on HFD was virtually indistinguishable from that of either the control animals, or FANKO mice fed a normal caloric chow diet. The team say the data indicated that “NAMPT plays an essential and specific role in adipose by facilitating weight gain in response to dietary fat.”

Further studies indicated that FANKO mice fed a HFD did naturally eat less, which could partly explain why they didn't become overweight, but the animals also exhibited changes in adipose tissue structure and function in response to their HFD, which prevented fat storage. “…upon transitioning to HFD, FANKO mice immediately reduced their food intake relative to controls,” the researchers comment. “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.…In the absence of NAMPT, adipocytes are unable to cope with the metabolic burden resulting in tissue dysfunction and ectopic lipid deposition in liver but not skeletal muscle.”

The HFD-fed FANKO mice were, perhaps surprisingly, more glucose tolerant than their control littermates. “…loss of adipose NAMPT profoundly alters the systemic response to high dietary fat intake by reprogramming patterns of substrate utilization, decreasing food intake, and improving glycemic control,” the team concludes.”

Interestingly, while the adipose tissue fibrosis and dysfunction in FANKO mice was reversed when the animals were switched back to a normal chow diet after four months of HFD, the animals retained their higher glucose tolerance.

The overall findings “indicate that adipose NAMPT plays an essential role in handling dietary lipid to modulate fat tissue plasticity, food intake, and systemic glucose homeostasis,” the authors state. “In the context of evolution, we believe adipose NAMPT would have been highly advantageous for efficiently accumulating fat mass from dietary fat. However, as evidenced by the significant association between NAMPT and obesity in humans, this program may now be a liability with modern lipid-laden diets.”

The team acknowledges that targeting NAMPT in humans may not represent a viable approach to obesity prevention or therapy. “NAMPT is expressed across numerous organ systems in which it plays critical roles in tissue-specific metabolism,” they write. Nevertheless, their findings, and future studies that provide new insights into how we become obese, may lead to the development of new, more targeted treatments for obesity and its consequences.

“Our ultimate goal is that by understanding these fundamental underpinnings of how we become obese, we can apply our findings to the development of novel treatment strategies for metabolic disease,” says Nørgaard Nielsen. The team suggests that their results do “establish the unequivocal necessity of NAMPT for adipose plasticity specifically in the context of high dietary fat….future studies identifying how adipose Nampt deficiency triggers reduced food intake and increased glucose tolerance could lead to a more targeted, clinically appealing approach.”