A novel mineralocorticoid receptor blocker, CS-3150, improves insulin resistance and reduces inflammation in db/db mice

Aldosterone plays a central role in regulating blood pressure and electrolyte balance, and emerging evidence implicates its involvement in metabolic disorders. This study evaluated the metabolic effects of CS-3150, a novel nonsteroidal and selective mineralocorticoid receptor (MR) antagonist, in genetically obese db/db mice. Mice were administered CS-3150 (3 mg/kg/day) for 8 weeks while maintained on a normal chow diet. Metabolic parameters, tissue morphology, inflammatory gene expression, and insulin signaling-assessed <i>via</i> Akt phosphorylation-were examined using standard biochemical and molecular techniques. CS-3150 treatment significantly improved insulin sensitivity (p < 0.05) without notable changes in fasting blood glucose or lipid profiles. However, CS-3150 markedly reduced adipocyte size, visceral fat accumulation, and hepatic lipid deposition (p < 0.01). These changes were accompanied by decreased macrophage infiltration (p < 0.01) and reduced expression of inflammatory markers, including <i>Vcam1, Sele</i>, and <i>Il6</i> in white adipose tissue (p < 0.05). <i>In vitro</i>, aldosterone impaired insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 hepatocytes, and C2C12 myotubes. CS-3150 treatment reversed this effect, whereas the traditional MR antagonist eplerenone failed to do so at equivalent concentrations. In conclusion, CS-3150 improved insulin sensitivity in obese diabetic mice, likely through attenuation of adipose inflammation, reduction in fat accumulation, and enhancement of insulin signaling. These findings support the potential of CS-3150 as a therapeutic agent for obesity-associated metabolic dysfunction.