Published Online
on April 21, 2008

A more recent version of this article appeared on April 29, 2008

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Submitted on November 1, 2007
Accepted on February 26, 2008

Mineralocorticoid Receptor Blockade Reverses Obesity-Related Changes in Expression of Adiponectin, Peroxisome Proliferator-Activated Receptor-, and Proinflammatory Adipokines

Christine Guo MD, Vincent Ricchiuti PhD, Bill Q. Lian MD, PhD, Tham M. Yao BSc, Patricia Coutinho BSc, José R. Romero PhD, Jianmin Li MS, Gordon H. Williams MD, and Gail K. Adler MD, PhD^*

From the Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital (C.G., V.R., T.M.Y., P.C., J.R.R., J.L., G.H.W., G.K.A.), and Department of Medicine, Mount Auburn Hospital (B.Q.L.), Harvard Medical School, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: gadler{at}partners.org.

Background—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.

Methods and Results—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-, monocyte chemoattractant protein-1, plasminogen activator inhibitor type 1, and macrophage protein CD68 increased, and expression of adiponectin and peroxisome proliferator-activated receptor- 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- and monocyte chemoattractant protein-1 and reduced mRNA and protein levels of peroxisome proliferator-activated receptor- and adiponectin, supporting a direct aldosterone effect on gene expression.

Conclusions—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.

Key words: adipose tissue • aldosterone • aldosterone antagonists • diabetes mellitus • inflammation • mineralocorticoid receptor • obesity

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Circulation 2008 117: 2169. [Extract] [Full Text]

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