Abstract 190: Activation of Angiotensin Type 2 Receptor Alters High-fat Diet-Induced Lipid Metabolism and Rescues Adipocyte Size Increase in Young Male Mice

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Recent studies demonstrated that the genetic deletion of the angiotensin type 2 receptor (AT2R) decreases adipocyte size and controls obesity, a major risk factor for metabolic syndrome. Current study was designed to investigate the effect of pharmacological activation of AT2R on adipocyte size. Male C57BL/6 mice (4-weeks old) were pretreated with the AT2R agonist C21 (0.3 mg/kg, daily i.p.) for 4 days. Thereafter the animals were placed on normal chow diet (ND) or high-fat diet (HFD) with concurrent drug treatment for next 10 days. In 10 days, the HFD significantly increased the body weight (ND:22+0.26 g vs HFD:24+0.40 g), epididymal fat pads weight (ND:0.23±0.03 g vs HFD:0.42±0.03 g), epididymal adipocyte size (ND:1407+176 μm2 vs HFD:2358+96 μm2), plasma free fatty acid (FFA) (ND:0.63+0.04 nmol/μL vs HFD:0.84+0.06 nmol/μL) and triglyceride (TG) (ND:0.31+0.01 nmol/μL vs HFD:0.40+0.03 nmol/μL). The pharmacological activation of AT2R rescued the HFD-induced increase in body weight (22+0.39 g), epididymal fat pads weight (0.30±0.02 g), epididymal adipocyte size (1831+95 μm2), plasma FFA (0.56+0.03 nmol/μL) and TG (0.18+0.02 nmol/μL). On one hand, HFD increased the protein expressions (measured by western blot) of the epididymal white adipose tissue (WAT) lipogenic regulators namely lipoprotein lipase (LPL) (142%), adipose fatty acid binding protein (FABP4) (199%), fatty acid synthase (FASN) (225%), peroxisome proliferator-activated receptor gamma (PPAR-γ) (176%). On the other hand, a differential regulation in the protein expressions of the epididymal WAT lipolytic regulators was observed. The HFD caused decrease in the protein expression of epididymal WAT adipose triglyceride lipase (ATGL) (62%) while increase in hormone-sensitive lipase (HSL) (191%) protein expression. C21 treatment altered all the HFD-induced changes in the protein expressions of LPL (83%), FABP4 (79%), FASN (54%), PPAR-γ (49%), ATGL (167%) and HSL (50%). In conclusion, the pharmacological activation of AT2R alters the HFD-induced lipid metabolism (lipogenesis and lipolysis) and rescues adipocyte size increase. This is the first study suggesting that the pharmacological activation of AT2R may serve as therapeutic strategy for controlling adipocyte size and obesity.