Angiotensin type 2 receptor activation promotes browning of white adipose tissue and brown adipogenesis

Brown adipose tissue dissipates energy in the form of heat. Recent studies have shown that adult humans possess both classical brown and beige adipocytes (brown-like adipocytes in white adipose tissue, WAT), and stimulating brown and beige adipocyte formation can be a new avenue to treat obesity. Angiotensin II (AngII) is a peptide hormone that plays important roles in energy metabolism via its angiotensin type 1 or type 2 receptors (AT1R and AT2R). Adipose tissue is a major source of AngII and expresses both types of its receptors, implying the autocrine and paracrine role of AngII in regulating adipose functions and self-remodeling. Here, based on the in vitro studies on primary cultures of mouse white adipocytes, we report that, AT2R activation, either by AngII or AT2R agonist (C21), induces white adipocyte browning, by increasing PPARγ expression, at least in part, via ERK1/2, PI3kinase/Akt and AMPK signaling pathways. It is also found that AngII–AT2R enhances brown adipogenesis. In the in vivo studies on mice, administration of AT1R antagonist (ZD7155) or AT2R agonist (C21) leads to the increase of WAT browning, body temperature and serum adiponectin, as well as the decrease of WAT mass and the serum levels of TNFα, triglycerides and free fatty acids. In addition, AT2R-induced browning effect is also observed in human white adipocytes, as evidenced by the increased UCP1 expression and oxygen consumption. Finally, we provide evidence that AT2R plays important roles in hormone T3-induced white adipose browning. This study, for the first time, reveals the browning and brown adipogenic effects of AT2R and suggests a potential therapeutic target to combat obesity and related metabolic disorders. Activating a hormone known to increase blood pressure may help to turn calorie-storing white fat into calorie-burning brown fat. Peng Chen from Nanyang Technological University in Singapore and colleagues observed a browning of mouse and human white fat cells when they boosted the activity of the type 2 receptor for the hormone angiotensin II, either by adding angiotensin II, a chemical activator of the type 2 receptor, or a drug that blocked the type 1 receptor (which has the indirect effect of sending more angiotensin II to activate the type 2 receptor). They then treated living mice in this way and saw more brown fat and higher body temperatures, indicative of increased energy expenditure. The findings point to a new possible therapeutic target for combating obesity, diabetes and related metabolic disorders.