Adipocytes Produce Aldosterone Through Calcineurin-Dependent Signaling Pathways: Implications in Diabetes Mellitus–Associated Obesity and Vascular Dysfunction
Abstract
We reported aldosterone as a novel adipocyte-derived factor that regulates vascular function. We aimed to investigate molecular mechanisms, signaling pathways, and functional significance of adipocyte-derived aldosterone and to test whether adipocyte-derived aldosterone is increased in diabetes mellitus–associated obesity, which contributes to vascular dysfunction. Studies were performed in the 3T3-L1 adipocyte cell line and mature adipocytes isolated from human and mouse (C57BL/6J) adipose tissue. Mesenteric arteries with and without perivascular fat and mature adipocytes were obtained from obese diabetic db/db and control db/+ mice. Aldosterone synthase (CYP11B2; mRNA and protein) was detected in 3T3-L1 and mature adipocytes, which secrete aldosterone basally and in response to angiotensin II (Ang II). In 3T3-L1 adipocytes, Ang II stimulation increased aldosterone secretion and CYP11B2 expression. Ang II effects were blunted by an Ang II type 1 receptor antagonist (candesartan) and inhibitors of calcineurin (cyclosporine A and FK506) and nuclear factor of activated T-cells (VIVIT). FAD286 (aldosterone synthase inhibitor) blunted adipocyte differentiation. In candesartan-treated db/db mice (1 mg/kg per day, 4 weeks) increased plasma aldosterone, CYP11B2 expression, and aldosterone secretion were reduced. Acetylcholine-induced relaxation in db/db mesenteric arteries containing perivascular fat was improved by eplerenone (mineralocorticoid receptor antagonist) without effect in db/+ mice. Adipocytes possess aldosterone synthase and produce aldosterone in an Ang II/Ang II type 1 receptor/calcineurin/nuclear factor of activated T-cells–dependent manner. Functionally adipocyte-derived aldosterone regulates adipocyte differentiation and vascular function in an autocrine and paracrine manner, respectively. These novel findings identify adipocytes as a putative link between aldosterone and vascular dysfunction in diabetes mellitus–associated obesity.
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The increased aldosterone production by adipocytes in obesity contributes to the vascular changes associated with this condition.
“Finally, the increased aldosterone production by adipocytes in obesity was shown to contribute to the vascular changes associated with this condition (54).”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [54]
Adipocyte-derived aldosterone has emerged as a new paradigm in linking obesity with vascular disease.
“For instance, adipocyte-derived aldosterone has emerged as a new paradigm in linking obesity with vascular disease (54).”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [54]
Adipocyte-derived aldosterone regulates vascular function in a paracrine manner.
“Moreover, this study revealed that adipocyte-derived aldosterone regulates vascular function in a paracrine manner.”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [54]
Adipocytes possess the components necessary for aldosterone synthesis.
“Adipocytes were found to possess the components necessary for aldosterone synthesis.”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [54]
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Self-citation
- Authors
- Briones, A. M., Nguyen Dinh Cat, A., Callera, G. E., Yogi, A., Burger, D., He, Y., Corrêa, J. W., Gagnon, A. M., Gomez-Sanchez, C. E., Gomez-Sanchez, E. P., Sorisky, A., Ooi, T. C., Ruzicka, M., Burns, K. D., & Touyz, R. M.
- Affiliations
- University of Ottawa (CA)
- From the Kidney Research Centre (A.M.B., A.N.D.C., G.E.C., A.Y., D.B., Y.H., J.W.C., K.D.B., R.M.T.), Chronic Disease Program (A.M.G., A.S., T.C.O.), Ottawa Hospital Research Institute, and Division of Nephrology, Department of Medicine (M.R.), University of Ottawa, Ontario, Canada; G.V. (Sonny) Montgomery Veterans Affairs and Division of Endocrinology, Department of Medicine, University of Mississippi Medical Centers, Jackson, MS (C.E.G.-S., E.P.G.-S.); Current address (A.M.B.): Departamento...
- ORCID
- Venue
- Hypertension
- Published
- 2012-05
- Volume
- 59
- Issue
- 5
- Pages
- 1069-1078
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2111017518
- Cited by
- 375
- References
- 39
- Citations by year
- 2026: 24 · 2025: 29 · 2024: 26 · 2023: 30 · 2022: 18 · 2021: 28 · 2020: 22 · 2019: 19 · 2018: 27 · 2017: 21 · 2016: 27 · 2015: 35 · 2014: 32 · 2013: 27 · 2012: 10
- FWCI
- 26.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- aldosterone synthase, calcineurin, NFAT, angiotensin II, angiotensin II type 1 receptor, adipogenesis, vascular dysfunction, db/db mice, perivascular adipose tissue, mesenteric arteries, acetylcholine-induced relaxation, mineralocorticoid receptor, candesartan, eplerenone, autocrine and paracrine signaling
- MeSH terms
- Aldosterone, Animals, Benzimidazoles, Biphenyl Compounds, Cells, Cultured, Diabetic Angiopathies, Disease Models, Animal, Humans, Mice, Inbred C57BL, Obesity, Random Allocation, Sensitivity and Specificity, Tetrazoles, Signal Transduction, Adipocytes, Calcineurin, Diabetes Complications, Mice
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