Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines

• Published in: Circulation (New York, N.Y.) N.Y.), 2008-04, Vol.117 (17), p.2253-2261
• Main Authors: Guo, Christine, Ricchiuti, Vincent, Lian, Bill Q, Yao, Tham M, Coutinho, Patricia, Romero, José R, Li, Jianmin, Williams, Gordon H, Adler, Gail K
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipokines - genetics; Adipokines - immunology; Adiponectin - genetics; Adiponectin - immunology; Adipose Tissue - drug effects; Adipose Tissue - immunology; Aldosterone - pharmacology; Animals; Biomarkers; Body Weight; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - immunology; Homeostasis - immunology; Inflammation - complications; Inflammation - drug therapy; Inflammation - immunology; Leptin - genetics; Leptin - immunology; Male; Mice; Mice, Mutant Strains; Mineralocorticoid Receptor Antagonists; Myocardium - immunology; Obesity - complications; Obesity - drug therapy; Obesity - immunology; PPAR gamma - genetics; PPAR gamma - immunology; Receptors, Mineralocorticoid - metabolism; RNA, Messenger - metabolism; Triglycerides - blood
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.107.748640

In obesity, decreases in adiponectin and increases in proinflammatory adipokines are associated with heart disease. Because adipocytes express mineralocorticoid receptor (MR) and MR blockade reduces cardiovascular inflammation and injury, we tested the hypothesis that MR blockade reduces inflammation and expression of proinflammatory cytokines in adipose tissue and increases adiponectin expression in adipose tissue and hearts of obese mice. We determined the effect of MR blockade (eplerenone, 100 mg/kg per day for 16 weeks) on gene expression in retroperitoneal adipose and heart tissue from obese, diabetic db/db mice (n=8) compared with untreated obese, diabetic db/db mice (n=10) and lean, nondiabetic db/+ littermates (n=11). Expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor type 1, and macrophage protein CD68 increased, and expression of adiponectin and peroxisome proliferator-activated receptor-gamma decreased in retroperitoneal adipose tissue from obese versus lean mice. In addition, adiponectin expression in heart was reduced in obese versus lean mice. MR blockade prevented these obesity-related changes in gene expression. Furthermore, treatment of undifferentiated preadipocytes with aldosterone (10(-8) mol/L for 24 hours) increased mRNA levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 and reduced mRNA and protein levels of peroxisome proliferator-activated receptor-gamma and adiponectin, supporting a direct aldosterone effect on gene expression. MR blockade reduced expression of proinflammatory and prothrombotic factors in adipose tissue and increased expression of adiponectin in heart and adipose tissue of obese, diabetic mice. These effects on adiponectin and adipokine gene expression may represent a novel mechanism for the cardioprotective effects of MR blockade.