Prevention of Adverse Metabolic Consequences of Adipocyte Dysfunction Using MR Antagonists

Adipocyte dysfunctions leading to obesity and associated cardiometabolic complications represent a strategic target to limit the spread of type 2 diabetes and obesity. The ligand-activated transcription factor mineralocorticoid receptor (MR) has been shown to regulate adipose tissue development and metabolism, playing an important role on adipogenesis, adipokine expression, and autophagy. Excessive activation of MR has been associated with dysfunctional adipose tissue and altered glucose homeostasis. Importantly, mice treated with MR antagonists show resistance against diet-induced obesity and glucose intolerance, suggesting that MR antagonists may find application for obese subjects with altered glucose homeostasis.Autophagy is a process that contributes to the turnover of proteins and cytoplasmic organelles and maintains cellular homeostasis. Interestingly, mice with adipose tissue- specific impairment of autophagy are protected against diet induced-weight gain, fat mass expansion, and insulin resistance, showing that defective autophagy protects against adipose tissue dysfunction and prevents development of obesity. Importantly, treatment of mice fed an obesogenic diet with MR antagonists decreases adipose tissue autophagic rate and confers protection from fat mass expansion and impaired glucose tolerance. Indeed, the ability of MR to regulate the autophagic process opens novel potential applications of MR antagonists for the treatment of adipose tissue dysfunction and obesity.