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Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis
Abstract
BACKGROUND: In obesity, the excessive synthesis of aldosterone contributes to the development and progression of metabolic and cardiovascular dysfunctions. Obesity-induced hyperaldosteronism is independent of the known regulators of aldosterone secretion, but reliant on unidentified adipocyte-derived factors. We hypothesized that the adipokine leptin is a direct regulator of aldosterone synthase (CYP11B2) expression and aldosterone release and promotes cardiovascular dysfunction via aldosterone-dependent mechanisms. METHODS AND RESULTS: Immunostaining of human adrenal cross-sections and adrenocortical cells revealed that adrenocortical cells coexpress CYP11B2 and leptin receptors. Measurements of adrenal CYP11B2 expression and plasma aldosterone levels showed that increases in endogenous (obesity) or exogenous (infusion) leptin dose-dependently raised CYP11B2 expression and aldosterone without elevating plasma angiotensin II, potassium or corticosterone. Neither angiotensin II receptors blockade nor α and β adrenergic receptors inhibition blunted leptin-induced aldosterone secretion. Identical results were obtained in cultured adrenocortical cells. Enhanced leptin signaling elevated CYP11B2 expression and plasma aldosterone, whereas deficiency in leptin or leptin receptors blunted obesity-induced increases in CYP11B2 and aldosterone, ruling out a role for obesity per se. Leptin increased intracellular calcium, elevated calmodulin and calmodulin-kinase II expression, whereas calcium chelation blunted leptin-mediated increases in CYP11B2, in adrenocortical cells. Mineralocorticoid receptor blockade blunted leptin-induced endothelial dysfunction and increases in cardiac fibrotic markers. CONCLUSIONS: Leptin is a newly described regulator of aldosterone synthesis that acts directly on adrenal glomerulosa cells to increase CYP11B2 expression and enhance aldosterone production via calcium-dependent mechanisms. Furthermore, leptin-mediated aldosterone secretion contributes to cardiovascular disease by promoting endothelial dysfunction and the expression of profibrotic markers in the heart.
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“Moreover, leptin adversely affects calcium handling in cardiomyocytes so as to impair myocardial relaxation, stimulates the synthesis of collagen inducing cardiac fibrosis by increasing aldosterone secretion, and enhances the sodium tubular reabsorption [95,96,97].”
From Dysregulated epicardial adipose tissue as a risk factor and potential therapeutic target of heart failure with preserved ejection fraction in diabetes (2022) · cites this paper as [96]
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Metadata
- Authors
- Huby, A.-C., Antonova, G., Groenendyk, J., Gomez-Sanchez, C. E., Bollag, W. B., Filosa, J. A., & de Chantemèle, E. J. B.
- Affiliations
- Augusta University (US)
- From Physiology Department, Medical College of Georgia at Georgia Regents University, Augusta (A.-C.H., G.A., J.G., W.B.B., J.A.F., E.J.D.d.C.); Charlie Norwood VA Medical Center, Augusta, GA (W.B.B.); Endocrine Section, G.V. (Sonny) Montgomery VA Medical Center, and University of Mississippi Medical Center, Jackson (C..E.G.-S.).
- Venue
- Circulation
- Published
- 2015-12
- Volume
- 132
- Issue
- 22
- Pages
- 2134-2145
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2206025985
- Cited by
- 376
- References
- 49
- Citations by year
- 2026: 34 · 2025: 41 · 2024: 37 · 2023: 34 · 2022: 44 · 2021: 32 · 2020: 36 · 2019: 31 · 2018: 37 · 2017: 29 · 2016: 18 · 2015: 1
- FWCI
- 24.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, aldosterone secretion, CYP11B2, aldosterone synthase, obesity, hyperaldosteronism, adrenal glomerulosa cells, adipokines, endothelial dysfunction, myocardial fibrosis, calcium signaling, calcium/calmodulin-dependent protein kinase II, mineralocorticoid receptor, cardiovascular disease
- MeSH terms
- Adrenal Cortex, Aldosterone, Animals, Cells, Cultured, Endothelium, Vascular, Female, Fibrosis, Heart Diseases, Humans, Mice, Inbred C57BL, Mice, Obese, Rats, Inbred WKY, Rats, Zucker, Adipocytes, Mice, Knockout, Leptin, Cell Line, Tumor, Mice, Rats
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