Targeting Mineralocorticoid Receptors in Diet-induced Hepatic Steatosis and Insulin Resistance

Mineralocorticoid receptor (MR) activation plays an important role in hepatic insulin resistance. However, the precise mechanisms by which MR activation promotes hepatic insulin resistance remains unclear. Therefore, we sought to investigate the roles and mechanisms by which MR activation promotes Western diet (WD)-induced hepatic steatosis and insulin resistance. Six-week-old C57BL6J mice were fed either mouse chow or a WD, high in saturated fat and refined carbohydrates, with or without the MR antagonist spironolactone (1 mg/kg/day) for 16 wk. WD feeding resulted in systemic insulin resistance at 8 and 16 wk. WD also induced impaired hepatic insulin metabolic signaling via phosphoinositide 3-kinases/protein kinase B pathways, which was associated with increased hepatic CD36, fatty acid transport proteins, fatty acid-binding protein-1, and hepatic steatosis. Meanwhile, consumption of a WD-induced hepatic mitochondria dysfunction, oxidative stress, and inflammatory responses. These abnormalities occurring in response to WD feeding were blunted with spironolactone treatment. Moreover, spironolactone promoted white adipose tissue browning and hepatic glucose transporter type 4 expression. These data suggest that enhanced hepatic MR signaling mediates diet-induced hepatic steatosis and dysregulation of adipose tissue browning, and subsequent hepatic mitochondria dysfunction, oxidative stress, inflammation, as well as hepatic insulin resistance.