Role of angiotensin type 2 receptor in improving lipid metabolism and preventing adiposity

Recent studies on mice with null mutation of the angiotensin type 2 receptor (AT₂R) gene have implicated the involvement of AT₂R in regulating adipocyte size and obesity, a major risk factor for metabolic syndrome. However, the outcome from these studies remains inconclusive. Therefore, current study was designed to test whether pharmacological activation of AT₂R regulates adiposity and lipid metabolism. Male mice (5-weeks old) were pre-treated with vehicle or AT₂R agonist (C21, 0.3 mg/kg, i.p., daily, for 4 days) and fed normal diet (ND). Then these animals were subdivided into ND and high-fat diet (HFD) regimen and concomitantly treated with vehicle or C21 through day 14. Vehicle-treated HFD-fed mice demonstrated an increase in epididymal white adipose tissue (eWAT) weight and adipocyte size, which were associated with increased eWAT expression of the lipogenic regulators, fatty acid binding protein and fatty acid synthase, decreased expression of adipose triglyceride lipase and increased expression of hormone-sensitive lipase. Interestingly, C21 pre-treatment altered HFD-induced changes in lipogenic and lipolytic regulators. C21 pre-treatment prevented decrease in expression of uncoupler protein-1 in brown adipose in HFD-fed mice, which was associated with increased core temperature. In addition, C21 pre-treatment ameliorated plasma-free fatty acids, triglycerides, insulin and tumor necrosis factor-α in HFD-fed mice. Ex-vivo study in isolated primary epididymal adipocytes revealed that C21 inhibits long chain fatty acid transporter, via a nitric oxide synthase/guanylate cyclase/protein kinase G-dependent pathway. Collectively, we propose pharmacological activation of AT₂R regulates fatty acid metabolism and thermogenesis and prevents HFD-induced adiposity in mice.