Pyruvate Kinase M2 Deficiency Promotes Brown Fat Adipogenesis in Vitro and Enhances Adaptive Thermogenesis in Vivo

Abstract

The prevalence of obesity and its comorbidities has sparked a worldwide concern to address rates of adipose tissue accrual. Pharmacological approaches to combat obesity have met with limited success despite intensive investments in their development. Although many differing strategies are being explored in cellular and molecular studies, many have proven ineffective at achieving long‐term positive outcomes. Thus, the search for novel approaches and new target must continue. Brown adipocytes are specialized to dissipate chemical energy as heat and are associated with improved metabolic phenotypes. Herein we demonstrate that altered expression of the glycolytic enzyme pyruvate kinase M2 (PKM2) promotes adipogenesis of mouse and human brown adipocytes. Additionally, modulation of PKM2 expression results in increased lipolysis through modulation of the activity of protein kinase A and hormone‐sensitive lipase (HSL). Importantly, PKM2 deficiency in brown adipocytes increases ATP turnover, and enhances basal and maximal mitochondrial respiration. Furthermore, mice with specific deletion of PKM2 in brown adipose tissue exhibited increased energy expenditure and resistance to cold‐induced alteration in core body temperature. Collectively, these findings identify PKM2 as a novel component of the molecular circuit that contributes to brown fat adipogenesis and adaptive thermogenesis, which may have potential therapeutic implications.Support or Funding InformationThis work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (R00DK100736) to A.B.