Pyruvate Kinase M2 Deficiency Enhances Brown Fat Adipogenesis and Activity

Abstract

In the last decade, development and regulation of brown adipose tissue (BAT) has gained traction due to its potential role in the protection against obesity and its associated disorders. Notably, BAT activity inversely correlates with overall adiposity. Brown fat-like adipocytes, that express the brown adipocyte-specific uncoupling protein 1, are interspersed in WAT of rodents and humans. These brown-like adipocytes exhibit many of the morphological and biochemical characteristics of classical brown adipocytes. Remarkably, brown-like transformation of WAT is associated with resistance to diet induced obesity in experimental mouse models. However, the mechanisms that regulate the browning of WAT remain incompletely understood. Recent studies have shown that inhibition of the glycolytic enzyme Pyruvate Kinase M2 (PKM2) promotes brown adipogenesis. Notably, PKM2 is an upstream regulator of the Wnt/β-catenin. Although the molecular mechanisms are yet to be determined, recent studies have shown that the Wnt/β-catenin regulates the differentiation of both, white and brown adipogenesis. Therefore, the main objective of the current study is to investigate the role of Wnt/β-catenin in mediating PKM2’s function in in brown adipogenesis and function. We demonstrate that PKM2 deficiency and pharmacological inhibition enhances brown fat activity via modulation of the Wnt/β-catenin signaling pathway. These findings identify PKM2 as a good target for therapeutic approaches aiming at overcoming the obesity epidemic and its comorbidities.