Mineralocorticoid Receptor Blockade Reverses Obesity-Related Changes in Expression of Adiponectin, Peroxisome Proliferator-Activated Receptor-γ, and Proinflammatory Adipokines
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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-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. 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.
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Mineralocorticoid receptors on adipocytes promote inflammatory adipokine expression, leading to lower insulin receptor expression and impaired insulin-induced glucose uptake.
“MRs on adipocytes promoted the expression of inflammatory adipokines (-), giving rise to lower insulin receptor expression and impaired insulin-induced glucose uptake ().”
From Glucose Metabolism Abnormalities in Cushing Syndrome: From Molecular Basis to Clinical Management (2017) · cites this paper as [176]
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References 55 · Cited by 342
- Authors
- Guo, C., Ricchiuti, V., Lian, B. Q., Yao, T. M., Coutinho, P., Romero, J. R., Li, J., Williams, G. H., & Adler, G. K.
- Affiliations
- Brigham and Women's Hospital (US)
- 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.
- Venue
- Circulation
- Published
- 2008-04-29
- Volume
- 117
- Issue
- 17
- Pages
- 2253-2261
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2746647
- OpenAlex
- W2102445277
- Cited by
- 342
- References
- 55
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 11 · 2023: 17 · 2022: 18 · 2021: 16 · 2020: 13 · 2019: 18 · 2018: 25 · 2017: 19 · 2016: 21 · 2015: 25 · 2014: 23 · 2013: 24 · 2012: 25
- FWCI
- 15.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL069208, HL-069208, R01HL063423, T32HL007609, HL063423)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-064841, R03DK064841)
- National Institute of Environmental Health Sciences (R21ES014462, ES014462)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- mineralocorticoid receptor blockade, eplerenone, obesity, adiponectin, PPARγ, adipose tissue inflammation, cardiac inflammation, TNF-α, MCP-1, plasminogen activator inhibitor-1, macrophages, aldosterone, preadipocytes, db/db mice, type 2 diabetes, cardioprotection, prothrombotic factors
- MeSH terms
- Adipose Tissue, Aldosterone, Mineralocorticoid Receptor Antagonists, Animals, Body Weight, Diabetes Mellitus, Experimental, Homeostasis, Inflammation, Male, Mice, Mutant Strains, Myocardium, Obesity, RNA, Messenger, Triglycerides, Biomarkers, Receptors, Mineralocorticoid, Leptin, 3T3-L1 Cells, PPAR gamma, Mice, Adiponectin, Adipokines
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