Targeting mineralocorticoid receptors to treat metabolic diseases via the adipocyte

The mineralocorticoid receptor (MR), classically known for its role in electrolyte homeostasis, has emerged since the early 2000s as a key regulator of adipocyte biology. MR activation induces oxidative stress and inflammation, promotes white adipogenesis, and suppresses brown fat differentiation, potentially contributing to obesity and metabolic syndrome (MetS). In mice, MR antagonists (MRAs) have shown beneficial metabolic effects by reversing adipose tissue dysfunctions, counteracting excessive expansion of fat depots, and enhancing brown adipose tissue (BAT) thermogenesis. Clinical translation remains limited, with inconsistent outcomes in individuals with overweight or obesity, and concerns about side effects of steroidal MRAs (sMRAs), particularly hyperkalemia. Nevertheless, recent data showed that MRAs are able to activate BAT in healthy individuals and in patients with familial partial lipodystrophy type 2 (FPLD2). Nonsteroidal MR antagonists (nsMRAs), such as finerenone, exhibit anti-inflammatory and antifibrotic properties in the kidney and heart, with improved safety profiles compared to sMRAs, and are currently being explored in metabolic disorders beyond cardiorenal disease. This review summarizes novel insights into MR function in adipose tissue and critically evaluates whether MR can still be considered a valid target to treat obesity and associated metabolic disorders.