Exercise-like effects by Estrogen-related receptor-gamma in muscle do not prevent insulin resistance in db/db mice

Dissecting exercise-mimicking pathways that can replicate the benefits of exercise in obesity and diabetes may lead to promising treatments for metabolic disorders. Muscle estrogen-related receptor gamma (ERR gamma) is induced by exercise, and when over-expressed in the skeletal muscle mimics exercise by stimulating glycolytic-to-oxidative myofiber switch, mitochondrial biogenesis and angiogenesis in lean mice. The objective of this study was to test whether muscle ERR gamma in obese mice mitigates weight gain and insulin resistance. To do so, ERR gamma was selectively over-expressed in the skeletal muscle of obese and diabetic db/db mice. Muscle ERR gamma over-expression successfully triggered glycolytic-to-oxidative myofiber switch, increased functional mitochondrial content and boosted vascular supply in the db/db mice. Despite aerobic remodeling, ERR gamma surprisingly failed to improve whole-body energy expenditure, block muscle accumulation of triglycerides, toxic diacylglycerols (DAG) and ceramides or suppress muscle PKC epsilon sarcolemmal translocation in db/db mice. Consequently, muscle ERR gamma did not mitigate impaired muscle insulin signaling or insulin resistance in these mice. In conclusion, obesity and diabetes in db/db mice are not amenable to selective ERR gamma-directed programming of classic exercise-like effects in the skeletal muscle. Other biochemical pathways or integrated whole-body effects of exercise may be critical for resisting diabetes and obesity.