Adipocytes Produce Aldosterone Through Calcineurin-Dependent Signaling Pathways

Abstract

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/ϩ 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/ϩ 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. (Hypertension. 2012;59:1069-1078.) • Online Data Supplement

Comparison of eplerenone and spironolactone for the treatment of primary aldosteronism

“…Brines et al [28] reported that adipocytes produce aldosterone, which regulates adipocyte differentiation and vascular function in an autocrine and paracrine manner. In addition, a higher prevalence of glycemic abnormalities and of the metabolic syndrome has been demonstrated in patients with PA compared with those with essential hypertension [29].…”

Cholesteryl Ester-Transfer Protein Inhibitors Stimulate Aldosterone Biosynthesis in Adipocytes through Nox-Dependent Processes

“…Reasons for probing adipocytes were 3-fold. First, we previously demonstrated that adipocytes have a functional renin angiotensin aldosterone system and produce aldosterone in a highly regulated manner (Briones et al, 2011(Briones et al, , 2012. Second, CETP inhibitors are lipid soluble and accumulate, to variable degrees, in adipocytes (Dalvie et al, 2008;Gotto et al, 2014).…”

“…We previously demonstrated that adipocytes possess the enzymatic machinery to synthesize mineralocorticoids and glucocorticoids, namely CYP11B2, CYP11B1, and steroidogenic acute regulatory protein (StAR), and that they produce aldosterone and corticosteroids in basal and stimulated conditions (Briones et al, 2011(Briones et al, , 2012. Adipocyte-derived aldosterone involves generation of reactive oxygen species (ROS) through Nox-dependent processes and plays a role in adipogenesis, adipocyte maturation, and adipokine production (Briones et al, 2012).…”

Adipocyte-Specific Mineralocorticoid Receptor Overexpression in Mice Is Associated With Metabolic Syndrome and Vascular Dysfunction: Role of Redox-Sensitive PKG-1 and Rho Kinase

“…MR is also expressed in nonepithelial cells, including cardiomyocytes (1), vascular cells (2,3) and macrophages (4,5), and has been implicated in pathological conditions such as heart failure, endothelial dysfunction, hypertension, insulin resistance, and obesity (6)(7)(8)(9)(10). Recently, MR has been identified in adipocytes (11)(12)(13)(14). The (patho)-physiological significance of adipocyte MR is unclear, although experimental and human studies have demonstrated increased expression of adipocyte MR in obesity, metabolic syndrome, and diabetes (6,14,15).…”

“…MR mediates effects of aldosterone and glucocorticoids, which in adipocytes regulate adipogenesis, adipocyte maturation, and adipokines production (12,(18)(19)(20). We recently demonstrated that adipocytes possess functionally active MR and have the machinery to produce aldosterone, processes that are increased in obesity-associated diabetes and influence vascular function (6,12,13).…”