Cited by 376Hormonal Regulation and HypertensionRenin-Angiotensin System StudiesAdipokines, Inflammation, and Metabolic Diseases

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Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis

Huby, Anne-Cécile, Antonova, Galina, Groenendyk, Jake, Gomez-Sanchez, Celso E., Bollag, Wendy B., Filosa, Jessica A., de Chantemèle, Eric J. Belin·2015·Circulation

DOI 10.1161/circulationaha.115.018226

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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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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.).
ORCID: Bollag, Wendy B.
Filosa, Jessica A.
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2015-12
Volume: 132
Issue: 22
Pages: 2134-2145
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.115.018226
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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Adipocyte-Derived Hormone Leptin Is a Direct Regulator of Aldosterone Secretion, Which Promotes Endothelial Dysfunction and Cardiac Fibrosis

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