Turning Up the Heat on Brown Fat: How NAD+ Boosts Metabolic Function

Despite common beliefs, not all fat in our bodies is bad. In addition to the well-known “bad” kind that stores fat cells and is implicated in overweight and obese individuals — also known as white fat — our bodies have evolved to contain a specialized fat that burns calories and supports the way we turn food into energy. This beneficial fat, called brown fat, is at its highest levels in infancy and drastically declines with increasing age.

A similar decline is seen with levels of a coenzyme required for all cells to function properly called nicotinamide adenine dinucleotide (NAD+). With age, NAD+ levels drop, leading to organ and tissue dysfunction, the deterioration of our bodies, and chronic disease development. One known way to elevate NAD+ levels is through its precursor, nicotinamide mononucleotide (NMN). With the similarities between NAD+ and brown fat reductions in mind, Yamaguchi and colleagues from Washington University School of Medicine in St. Louis intended to further elucidate the relationship between the two and potentially mitigate the ever-increasing rates of obesity seen worldwide — and they did, using the NAD+ precursor called nicotinamide mononucleotide (NMN).

Good fat, bad fat, brown fat, white fat

Brown fat, also known as brown adipose tissue (BAT), contains high amounts of the energy-producing mitochondria, providing the tissue with its copper-brown color. The mitochondria found in BAT act as little engines that create heat from energy — also known as thermogenesis. It was once thought that only infants had brown fat, as they can’t maintain their body temperature through shivering, using their heat-producing packets of brown fat to keep them warm. Now, it’s known that adults also carry brown fat — albeit in much smaller amounts, especially in cases of obesity or increasing age. Higher amounts of BAT are linked to reductions in obesity, as approximately 20% of energy expenditure can be attributed to thermogenesis.

Although brown fat is crucial for thermogenesis, white adipose tissue (WAT) also plays a role in regulating this energy-burning process. White fat participates in lipolysis, releasing free fatty acids into circulation and providing the fuel for BAT to activate. WAT also secretes adiponectin and leptin, which are hormones that regulate glucose metabolism, energy balance, and satiety. 

While white fat is a leading source of obesity-related inflammation and metabolic dysfunction, the breakdown of white fat cells — which occurs during weight loss — is necessary for BAT to function properly. Research has found that prolonged cold exposure increases lipolysis from white fat, which upregulates adiponectin and leptin and stimulates brown fat activation. Although it’s clear that brown fat is the more beneficial of the two, this suggests that both BAT and WAT activity are vital for maintaining thermogenic regulation.

Maintaining metabolic mastery with brown fat

The metabolism-boosting effects of BAT are mediated by a unique mitochondrial protein called uncoupling protein 1 (UCP1). This protein causes the mitochondria to release energy as heat, rather than the cellular version of energy called ATP. With increasing age or obesity, mitochondrial function declines, causing reduced UCP1 activity and, in turn, reduced brown fat activation.

Another factor involved with brown fat activation is the stimulation of β-adrenergic receptors. These receptors are dysfunctional in obesity, resulting in impaired lipolysis — the breakdown of fats into smaller free fatty acids. Notably, lipolysis plays an essential role in BAT-related thermogenesis, as BAT uses these free fatty acids as fuel for UCP1 to do its job.

One well-known way to increase brown fat is through cold exposure, which activates BAT, burning energy to create heat in an attempt to warm the body. Also, exercise and fasting boost brown fat by stimulating the production of the metabolism-supporting hormone called irisin and increasing UCP1 activity in white fat cells, respectively. These pathways can also be triggered by consuming compounds like berberine, curcumin, resveratrol, and NMN. As brown fat may play a vital role in reducing obesity rates, researchers have aimed to uncover how exactly this fat-burning tissue relates to NAD+ levels in the body.

The necessity of NAMPT: the enzyme behind it all 

In this study, Yamaguchi and colleagues looked at the relationship between NAD+ levels, brown fat, and NAMPT — an enzyme required to synthesize a precursor to NAD+ in the body called nicotinamide mononucleotide (NMN). Just as NAD+ levels decline with age, so does NAMPT activity. After being released from adipose tissue, NAMPT travels to other organs and tissues, producing NMN to be converted into NAD+. 

Because of the essentiality of NAMPT in producing NAD+, the research team looked at the effects of eliminating the enzyme in two types of mice. The first, called ANKO mice, had NAMPT removed from all of their adipocytes (fat cells) — both brown and white. The second set, referred to as BANKO mice, only had NAMPT activity removed from the brown fat cells. 

In healthy control mice, cold exposure nearly doubled their NAD+ levels, in addition to boosting NAMPT and UCP1 activity. However, these beneficial metabolic outcomes were not seen in the mice without NAMPT. After exposure to cold conditions, prolonged fasting, or β-adrenergic receptor stimulation — all of which should boost NAD+ and thermogenesis — the ANKO mice had reduced NAD+, impaired thermogenesis, reduced mitochondrial function, and low lipolysis and UCP1 activity. These mice also were intolerant to the cold, indicating that the heat-generating brown fat was inactive. 

In contrast, BANKO mice — the ones that lack NAMPT only in their brown fat — maintained their thermogenic responses to these conditions, despite exhibiting similar metabolic and mitochondrial abnormalities. This suggests that NAMPT deletion in brown fat alone does not affect thermogenesis, furthering the hypothesis that WAT plays a role in stimulating BAT’s heat production — which is all mediated by NAD+. Essentially, NAMPT deletion in white fat cells leads to inadequate NAD+, reducing WAT’s lipolytic activity and limiting the free fatty acids available for BAT to use as thermogenic fuel. But, NAMPT deletion solely in brown fat cells doesn’t cause the same dysfunction — active lipolysis from white fat cells can pick up the slack, so to speak. However, if one doesn’t have adequate lipolytic activity — for example, in obesity or older age — energy expenditure through thermogenesis would still be dysregulated. And that’s where supplemental NMN comes in.

BATter up: NMN hits a home run for brown fat 

After teasing out the differences between these NAMPT-deleted mice, Yamaguchi and colleagues administered NMN to the ANKO mice. They found that NMN ameliorated the metabolic and mitochondrial dysfunction that arose after eliminating NAMPT, including increasing NAD+ in the fat cells, boosting mitochondrial function, and restoring gene activity related to thermogenesis and lipolysis. These NMN-treated mice also regained their cold tolerance abilities, indicating restored brown fat functionality. 

Taken together, these results indicate that low NAD+ levels in white fat cells markedly alter whole-body metabolic and thermogenic function by limiting brown fat activation. In cases of obesity, increasing age, or other metabolic disorders, supplemental NMN may be able to restore these lost thermogenic abilities, potentially leading to weight reduction and healthier metabolic function.

Although this study was done with mice, the research team did find inklings of hope that these results could be applied to humans. “The potential translation of these results to humans is supported by our observation that cold-induced BAT activation and UCP1 expression are accompanied by increased NAMPT expression in people”, the authors conclude, after looking at brown fat levels in human adipose tissue. While we don’t know for sure if NMN can reduce obesity in humans, we do know that boosting brown fat activity is linked to increased energy expenditure — estimates range from an additional 100 to 400 calories burned per day — and better metabolic control. Since we’ll have to wait for research in humans to fully elucidate the weight loss potential of NMN, for now, a cold shower per day may help to keep the doctor away.

References:

Chen KY, Brychta RJ, Abdul Sater Z, et al. Opportunities and challenges in the therapeutic activation of human energy expenditure and thermogenesis to manage obesity. J Biol Chem. 2020;295(7):1926-1942. doi:10.1074/jbc.REV119.007363

Mancuso P, Bouchard B. The Impact of Aging on Adipose Function and Adipokine Synthesis. Front Endocrinol (Lausanne). 2019;10:137. Published 2019 Mar 11. doi:10.3389/fendo.2019.00137

Yamaguchi S, Franczyk MP, Chondronikola M, et al. Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice. Proc Natl Acad Sci U S A. 2019;116(47):23822-23828. doi:10.1073/pnas.1909917116