Mineralocorticoid receptor antagonism induces browning of white adipose tissue through impairment of autophagy and prevents adipocyte dysfunction in high‐fat‐diet‐fed mice

Abstract

The mineralocorticoid receptor (MR) controls adipocyte function, but its role in the conversion of white adipose tissue (WAT) into thermogenic fat has not been elucidated. We investigated responses to the MR antagonists spironolactone (spiro; 20 mg/kg/d) and drospirenone (DRSP; 6 mg/kg/d) in C57BL/6 mice fed a high-fat (HF) diet for 90 d. DRSP and spiro curbed HF diet-induced impairment in glucose tolerance, and prevented body weight gain and white fat expansion. Notably, either MR antagonist induced up-regulation of brown adipocyte-specific transcripts and markedly increased protein levels of uncoupling protein 1 (UCP1) in visceral and inguinal fat depots when compared with the HF diet group. Positron emission tomography and magnetic resonance spectroscopy confirmed acquisition of brown fat features in WAT. Interestingly, MR antagonists markedly reduced the autophagic rate both in murine preadipocytes in vitro (10(-5) M) and in WAT depots in vivo, with a concomitant increase in UCP1 protein expression. Moreover, the autophagy repressor bafilomycin A1 (10(-8) M) mimicked the effect of MR antagonists, increasing UCP1 protein expression in primary preadipocytes. Hence, we showed that adipocyte MR regulates brown remodeling of WAT through a modulation of autophagy. These results provide a rationale for the use of MR antagonists to prevent the adverse metabolic consequences of adipocyte dysfunction.

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

“…Indeed, aldosterone activation of mineralocorticoid receptors promotes adipocytes expansion and differentiation toward a proinflammatory phenotype. 41,42 Hence the concept of an endocrine loop between adipocytes and adrenal cells, where adipocyte-derived leptin drives aldosterone production 1α1 (A, D), collagen 3α1 (B, E), and periostin (B, E) gene expression in the heart of Balb/c (A-C) and ob/ob mice (D-F) treated or not with leptin (0.9 mg/kg/d) for 7 days, in the presence or absence of spironolactone (100 mg/kg/d 2+ channels in chromaffin cells, further studies are required to determine the mechanisms whereby leptin increases intracellular Ca 2+ in adrenocortical cells. A main characteristic of obesity is the development of a progressive resistance to the anorexigenic effects of leptin, which further promotes body weight gain and metabolic dysfunction.…”

FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes

“…17,18 Consistently, pharmacological inhibition of autophagy prevented body weight gain and fat mass expansion, protecting against metabolic syndrome such as glucose intolerance and insulin resistance. 15,19 These findings underscore autophagy as an important player in adiposity regulation.…”

Cellular mechanisms of MR regulation of adipose tissue physiology and pathophysiology

“…Pharmacological MR antagonism has been shown to counteract dysfunctional metabolism of adipose tissue (Guo et al 2008, Hirata et al 2009, Wada et al 2010. Remarkably, conversion of white into brown adipose tissue, a process induced by MR blockade, takes part in the anti-obesity effects of MR antagonism (Armani et al 2014a).…”