title: 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.
authors.affiliation: Kidney Research Centre, Ottawa Hospital Research Institute, and Division of Nephrology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Briones
authors.forename: Aurelie
authors.initials: A
authors.lastname: Nguyen Dinh Cat
authors.forename: Glaucia E
authors.initials: GE
authors.lastname: Callera
authors.forename: Alvaro
authors.initials: A
authors.lastname: Yogi
authors.forename: Dylan
authors.initials: D
authors.lastname: Burger
authors.forename: Ying
authors.initials: Y
authors.lastname: He
authors.forename: Jose W
authors.initials: JW
authors.lastname: Corrêa
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Gagnon
authors.forename: Celso E
authors.initials: CE
authors.lastname: Gomez-Sanchez
authors.forename: Elise P
authors.initials: EP
authors.lastname: Gomez-Sanchez
authors.forename: Alexander
authors.initials: A
authors.lastname: Sorisky
authors.forename: Teik Chye
authors.initials: TC
authors.lastname: Ooi
authors.forename: Marcel
authors.initials: M
authors.lastname: Ruzicka
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burns
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D019703:Calcineurin / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000378:metabolism*; D011897:Random Allocation; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000450:Aldosterone; D019703:Calcineurin; C081643:candesartan