Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma

To clarify the mechanism of the effects of angiotensin II AT(1) receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT(1) receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum leptin levels and epididymal leptin mRNA, increased serum adiponectin levels and epididymal adiponectin mRNA, decreased epididymal tumor necrosis factor alpha (TNFalpha) mRNA, and increased fatty acid synthase mRNA. Considered free of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist activity, Candesartan cilexetil increased epididymal expression of PPARgamma mRNA. The effects of Candesartan cilexetil on adipokine production and release may be attributable to PPARgamma activation and/or decrease in adipocyte cell size. In addition, Candesartan cilexetil treatment increased the expression of epididymal angiotensin II AT(2) receptor mRNA and protein and decreased the expression of renin receptor mRNA. These results suggest that Candesartan cilexetil influences lipid metabolism in adipose tissue by promoting adipose tissue rearrangement and modulating adipokine expression and release. These effects are probably consequences of local angiotensin II AT(1) receptor inhibition, angiotensin II AT(2) receptor stimulation, and perhaps additional angiotensin II-independent mechanisms. Our results indicate that the activity of local renin-angiotensin system plays an important role in adipose tissue metabolism. The decrease in the pro-inflammatory cytokine TNFalpha and the increase in the anti-inflammatory adipokine adiponectin indicate that Candesartan cilexetil may exert significant anti-inflammatory properties.