Abstract 465: AT 2 Receptor Signaling Plays An Important Role In Conversion Of From White To Beige Fat

Abstract

Background: We have previously reported that treatment with angiotensin II type-2 (AT 2 ) receptor agonist (compound 21; C21) ameliorated insulin resistance with the improvement of adipocyte dysfunction in obese type 2 diabetic mouse model, KKAy. Until quite recently, adipose tissue has been divided into two groups that have directory-opposed capacities; white adipose tissue is best known for its role in energy store, while brown adipose tissue functions for energy expenditure (thermogenesis). In addition, new clusters of adipocyte with thermogenic capability have been discovered in white adipose tissue, which are distinct origins from brown adipose tissue. These adipocytes have been named ‘beige’. However, the role of AT 2 receptor signaling in white-to-beige fat conversion is not known. Methods: KKAy mice were subjected to i.p. injection of C21 (10ug/kg/day) for 2 weeks. After the treatment, the expression of thermogenic genes (Ucp1, Cidea, Pgc1α) in adipose tissue were determined with real-time RT-PCR. Next, we examined the difference in conversion from white to beige fat between wild-type (WT) mice and AT 2 receptor knockout (AT 2 KO) mice. Eight-week-old mice were fed a high-fat and high-cholesterol diet (HFCD) (10% coconut oil + 1.25% cholesterol) for 2 weeks. To examine the effect of exercise on fat conversion, 9-week-old mice were forced swim test (2 minх3 times/day) for 7days. After the swim test, mice were sacrificed for examinations. Results: In KKAy mice, treatment of C21 increased the expression of thermogenic genes in subcutaneous fat, but not in visceral fat. Adipose tissue weight was not changed by treatment of C21. In AT 2 KO mice fed HFCD for 2 weeks, visceral fat was greater than that in WT mice, but subcutaneous fat was not. The expression of thermogenic genes in subcutaneous fat was lower in AT 2 KO mice than in WT mice. In both mice, swim exercise increased the expression of thermogenic genes; however, the up-regulation of these genes in AT 2 KO mice did not reach the level of that in WT mice. Conclusion: These results suggest that AT 2 receptor signaling has an important role in white-to-beige fat conversion, and therefore AT 2 receptor signaling might be a potential therapeutic target for lipid metabolic disorders.