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

Abstract

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 (nϭ8) compared with untreated obese, diabetic db/db mice (nϭ10) and lean, nondiabetic db/ϩ littermates (nϭ11). 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 Ϫ8 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 proliferatoractivated 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.

Renin‐Angiotensin‐Aldosterone System, Glucose Metabolism and Incident Type 2 Diabetes Mellitus: MESA

“…Aldosterone inhibits insulin signaling and insulin‐stimulated glucose uptake via glut‐4 translocation in adipocytes, skeletal muscle, and vascular smooth muscle cells, as well as a reduction in adiponectin and peroxisome proliferator‐activated receptor‐gamma 3, 4. Aldosterone impairs β‐cell function and insulin secretion, in preclinical models through blunted glucose‐stimulated insulin secretion, moreover, in aldosterone synthase deficient mice glucose‐stimulated insulin secretion is markedly increased 18.…”

“…Thus, novel preventive intervention targets are of paramount importance, one potential target is the renin‐angiotensin‐aldosterone (RAAS). Aldosterone can impair insulin secretion and sensitivity, both of these actions are critical factors in the development of type 2 diabetes mellitus 2, 3, 4. In a German case‐control study, type 2 diabetes mellitus was more prevalent in subjects with primary aldosteronism (a state of high aldosterone, low angiotensin II and low plasma renin activity [PRA], most commonly because of bilateral adrenal gland enlargement or adrenal adenomas) with hypertension than in hypertensive controls 5.…”

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…11 -HSD2, whilst consistently lower than 11 -HSD1 was also reduced in adipose from obese women (Engeli et al, 2004) and may be expressed predominantly in the stromal compartment M a n u s c r i p t 8 of human visceral fat (Lee et al, 2008). This would make sense as aldosterone has been implicated in preadipocyte differentiation and adipokine expression in adipose, among other functions (Guo et al, 2008, Hirata et al, 2009. If confirmed, this may also account for the increased cortisone levels found in the portal vein (along with intestinal 11 -HSD2) of obese humans (Basu et al, 2008).…”

Marine natural product des-O-methyllasiodiplodin effectively lowers the blood glucose level in db/db mice via ameliorating inflammation

“…MR activation mediates inflammation, proliferation and fibrosis [29,39,40] , while MR blockade exhibits beneficial effects on cardiovascular morbidity and mortality in patients with heart failure [41,42] . Recent studies have also shown that MR antagonists improve adipocyte dysfunction and insulin resistance in obese mice [31][32][33] . The two MR antagonists, Spir and Eple, have been used clinically as antihypertensive drugs [41,42] .…”

“…Spironolactone (Spir) and eplerenone (Eple), known MR antagonists, have been shown to be useful in the treatment of hypertension and heart failure [29,30] , the reversal of obesity-related changes in pro-inflammatory adipokines and the amelioration of adipocyte dysfunction and insulin resistance [31][32][33] . In addition, the production of pro-inflammatory factors such as TNF-α, MCP-1, and IL-6 was attenuated by Eple both in liver and adipose tissue via the suppression of reactive oxygen species (ROS) [33] , and Spir improved glucose and lipid metabolism by ameliorating inflammation in high-fat and high-fructose diet mice [31] .…”