Molecular Control of Adipose Cell Fate and Energy Metabolism

 

Adipose tissues serve as central regulators of energy homeostasis. Two types of adipose tissue are found in mammals: white adipose tissue (WAT) and brown adipose tissue (BAT). While WAT functions primarily as a store of excess energy, the latter possesses characteristics that facilitate the dissipation of chemical energy through heat, in a process referred to as non-shivering thermogenesis. The remarkable oxidative capacity of brown fat to dissipate and repurpose excess chemical energy has prompted our lab to closer examine the links between BAT, obesity, and metabolic disorders.

 

Fundamentally, obesity is the result of energy intake chronically exceeding energy expenditure. Notwithstanding, the reality of this simple formula is much more nuanced as energy can be consumed in the form of physical activity, basal metabolism, as well as adaptive thermogenesis.  Deposits of BAT have been found to alter thermogenic activity at a basal state; therefore BAT recruitment, activation, and/or proliferation have particular relevance to counteracting obesity among other metabolic syndromes, such as diabetes (Fig. 1). We hope to lay the groundwork for novel therapeutic interventions of these increasingly prevalent disorders.

 

Brown adipose tissue was initially identified as a defense against hypothermia in infants who do not shiver and must generate heat through thermogenesis. Recent studies identified two types of thermogenic adipocytes: “classical brown adipocytes” and “beige adipocytes”. Classical brown adipocytes develop prenatally and exist predominantly in dedicated BAT depots of rodents and infants, such as the interscapular regions (Fig. 2). The infant interscapular BAT depots eventually disappear in adult humans. In contrast, beige adipocytes are a “recruitable” form of thermogenic adipocytes that arise postnatally in response to certain external cues, such as chronic cold exposure, long-term treatment with Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) agonists, exercise, cancer cachexia, burn injury, and bariatric surgery. This “recruitable” form has been of particular interest to us, as recent studies indicate increased beige fat mass is closely associated with the improvement of systemic glucose homeostasis and insulin sensitivity in several rodent models.

 

Remarkably, emerging research suggests the anti-diabetic effects of beige fat recruitment is distinctly uncoupled from its anti-obesity effects. By studying targets such as PRDM16 (PR-domain containing 16), a transcriptional co-activator of brown/beige fat development, and its co-activator, EHMT1, we found that improvements in whole-body glucose homeostasis and insulin sensitivity were disproportional to body-weight loss. This finding could provide insight into novel treatments of type 2 diabetes in the coming years. Our lab is currently trying to understand the mechanism by which increased beige fat mass leads to an improvement in systemic glucose homeostasis. Ultimately, we aim to decode the transcriptional and epigenetic networks that control the development and function of brown adipose cells, and to study their functional roles in metabolism and systemic regulation.