A Synthetic ERR Agonist Alleviates Metabolic Syndrome

Physical exercise induces physiological adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the ERRa, b and g nuclear receptors that activates an acute aerobic exercise program. Here, we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332 and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. Significance Statement An estrogen receptor-related orphan receptor (ERR) agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.