Researchers at NYU Langone have discovered that peroxisome proliferator activated receptor gamma (PPARg), a key regulator of adipogenesis, shifts function as we age, suggesting that targeting it could have an impact on metabolic function and longevity.

Mechanisms of Adipose Biology

In midlife, white fat accumulates, thermogenic function diminishes, and the likelihood of obesity and metabolic disease increases. To uncover the mechanisms driving these changes, Elisabetta Mueller, PhD, associate professor in the Department of Medicine at NYU Langone, is zeroing in on signature factors that regulate adipose biology at different life stages. Her mouse-model findings are revealing possible pathways that, if activated, could reverse age-related metabolic decline.

The Evolving Variegation of Fat

Two discoveries in the past decade—that both brown fat and newly identified beige adipocytes persist in adulthood—have led to a deeper understanding of fat tissue biology. This, in turn, has opened promising avenues of research that could have huge implications for aging. Dr. Mueller and her team are at the forefront of this research, studying the cascade of molecular events that determine adipogenesis and calorie utilization throughout life.

Adipose tissue is critical for energy homeostasis at any age. White fat stores energy, brown fat burns it, and beige fat switches back and forth from burning to storing depending on conditions in the body. But in older populations, researchers see decreased brown and beige fat cell function, while white adipocytes accumulate in the visceral cavity. The combined effect is metabolic dysfunction that often leads to obesity, diabetes, and other diseases.

The Master Fat Regulator

One of the key regulators of adipocyte differentiation, and a focus of Mueller’s lab, is the nuclear receptor PPARg, which is required for the development of all types of fat cells and functions as a regulator of both white and brown gene programs in adipocytes. “Given the importance of PPARg in fat tissue biology, we sought to determine this receptor’s role in aging-associated metabolic decline,” says Dr. Mueller. In a recent study, her team found that, compared with controls, middle-aged mice with ablation of PPARg in subcutaneous fat tissue had more white fat composed of larger adipocytes, increased insulin resistance, decreased thermogenesis, reduced levels of brown fat genes, and disadvantageous changes to several other metabolic indicators.

Conversely, PPARg suppression in young mice yielded much different results, namely an abnormal decrease in the amount of fat that was associated with a lipoatrophic phenotype. Along with the findings of other comparative studies, the data suggest that in young mice, PPARg’s main role is to maintain lipogenic functions, whereas in aging mice, PPARg’s job appears to shift to managing energy expenditure with the lipogenic functions taken over by related transcription factors. These results provide a new rationale for targeting PPARg in aging.

“This is the first evidence that, during aging, PPARg function in subcutaneous adipose tissue may be primarily to control energy expenditure,” says Dr. Mueller. “This receptor has an important role in aging, and its activation could lead to beneficial effects in age-associated metabolic disease.” The team is now looking for compounds that activate PPARg and testing their impact on health span and longevity. Dr. Mueller expects the first findings from this research will be published early next year.