Regulation of Brown Adipose Tissue and Beige Fat by the Adenosine A2B Receptor 8.5.5

Abstract

Pandemic obesity and its associated co-morbidities like type 2 diabetes, coronary heart disease or stroke is one of the biggest contemporary health problems and there is an urgent need for novel pharmacological treatment. Brown adipose tissue (BAT) is specialized in dissipating energy in the form of heat by uncoupling ATP synthesis due to its unique uncoupling protein 1 (UCP1). BAT abundance is correlated with leanness in humans and, thereby, BAT is a pharmaceutical target for an anti-obesity therapy. Adenosine is a novel alternative activator of human and brown adipocytes. The enigmatic Gs-protein-coupled adenosine A2B receptor is abundantly expressed in murine BAT. Here, we analyzed the role of the A2B receptor in BAT function in a model of diet-induced obesity. Adipose tissue-specific ablation of A2B reduced BAT energy expenditure (EE) in mice, whereas specific pharmacological stimulation of A2B ameliorated obesity concomitant with improved glucose homeostasis. Additionally, A2B activation promoted browning of inguinal WAT together with a reduced pro-inflammatory phenotype. In humans, high A2B expression correlated with high BAT activity and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment of primary human brown adipocytes resulted in elevated intracellular cAMP levels and increased oxygen consumption, whereas A2B stimulation of primary human white adipocytes promoted upregulation of thermogenic genes. Taken together, our results propose the adenosine A2B receptor as novel target with great potential to increase EE from BAT/brown adipocytes along with promoting browning of white fat. 8.5.5