PKM2: A Novel Therapeutic Target for the Prevention and Treatment of Obesity

The obesity epidemic continues to be a growing concern as it closely parallels with the exponential rise of associated co-morbidities including cardiovascular disease, type 2 diabetes, and other metabolic diseases. Furthermore, this epidemic has harnessed a wide interest to investigate dynamics of adipose tissue and its function. Although pharmaceuticals targeting weight loss and obesity are currently available, safety concern and off-target side effects propel the need for novel prevention and treatment options. In the last decade, development and regulation of brown adipose tissue (BAT) has become an attractive therapeutic strategy to promote weight loss and improve metabolic homeostasis. Additionally, recent studies have identified the glycolytic enzyme pyruvate kinase M2 (PKM2), as a novel regulator of brown adipogenesis and the browning of white adipose tissue (WAT). However, the molecular mechanisms remain to be elucidated. The current study investigates the role of β-catenin and its downstream target high mobility group AThook 2 (HMGA2) in mediating PKM2’srole in the browning of WAT. We demonstrate that PKM2 deficiency promotes the browning of white primary pre-adipocytes via modulation of the βcatenin/HMGA2 axis. Disruption of the β-catenin/HMGA2 signaling pathway abolished the effects of PKM2 deficiency on the browning of white adipocyte. While these findings are still preliminary, our study suggests that targeting PKM2 could constitute a strategy to prevent excess fat accumulation, enhance whole body energy expenditure, and improve glycemic control.