Adipose Tissue Dysfunction in Obesity: Role of Mineralocorticoid Receptor

Abstract

The mineralocorticoid receptor (MR) acts as an essential regulator of blood pressure, volume status, and electrolyte balance. However, in recent decades, a growing body of evidence has suggested that MR may also have a role in mediating pro-inflammatory, pro-oxidative, and pro-fibrotic changes in several target organs, including the adipose tissue. The finding that MR is overexpressed in the adipose tissue of patients with obesity has led to the hypothesis that this receptor can contribute to adipokine dysregulation and low-grade chronic inflammation, alterations that are linked to the development of obesity-related metabolic and cardiovascular complications. Moreover, several studies in animal models have investigated the role of MR antagonists (MRAs) in preventing the metabolic alterations observed in obesity. In the present review we will focus on the potential mechanisms by which MR activation can contribute to adipose tissue dysfunction in obesity and on the possible beneficial effects of MRAs in this setting.

Keywords: adipose tissue dysfunction; inflammation; insulin resistance; metabolic syndrome; mineralocorticoid receptor; obesity; oxidative stress.

Figure 1

Adipose tissue dysfunction in obesity. In obesity, WAT responds to calorie overload mainly through adipocyte hypertrophy. This leads to local hypoxia, cell stress and death, oxidative stress, and increased secretion of pro-inflammatory cytokines with subsequent infiltration of macrophages and development of chronic low-grade inflammation. Moreover, hypertrophic adipocytes display an impaired secretion of insulin-sensitizing molecules, such as adiponectin, and an increased release of FFA. All these changes, together with BAT dysfunction and impaired browning of WAT, eventually lead to insulin resistance, ectopic fat deposition, and metabolic syndrome. Abbreviations: BAT, brown adipose tissue; FFA: free fatty acids; HIF-1α: hypoxia inducible factor-1α; UCP-1: uncoupling protein-1; WAT: white adipose tissue.

Figure 2

Contribution of MR to adipose tissue inflammation. The activation of MR, either by aldosterone or by cortisol, leads to adipocyte hypertrophy, which in turn causes cell stress and death and local hypoxia. Moreover, hypertrophic adipocytes display an impaired secretion of adipokines, with an increased release of pro-inflammatory molecules. These changes promote the infiltration of macrophages and their polarization shift to a M1 phenotype. Finally, MR activation is linked to mitochondrial dysfunction and enhanced ROS production, which contribute to oxidative stress, another important pro-inflammatory stimulus. Abbreviations: MR, mineralocorticoid receptor; ROS: reactive oxygen species.