title: 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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Huby
authors.affiliation: 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.).
authors.forename: Galina
authors.initials: G
authors.lastname: Antonova
authors.affiliation: 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.).
authors.forename: Jake
authors.initials: J
authors.lastname: Groenendyk
authors.affiliation: 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.).
authors.forename: Celso E
authors.initials: CE
authors.lastname: Gomez-Sanchez
authors.affiliation: 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.).
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Bollag
authors.affiliation: 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.).
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Filosa
authors.affiliation: 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.). ebelindechanteme@gru.edu.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Belin de Chantemèle
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D005355:Fibrosis / Q000473:pathology; D006331:Heart Diseases / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D020738:Leptin / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D051381:Rats; D011921:Rats, Inbred WKY; D011924:Rats, Zucker
chemical_list: D020738:Leptin; D000450:Aldosterone
keywords: CYP11B2; adrenal glands; aldosterone; endothelium; heart; leptin; obesity