Exendin-4 increases oxygen consumption and thermogenic gene expression in muscle cells

Glucagon-like peptide-1 (GLP1) has many anti-diabetic actions and also increases energy expenditure in vivo. As skeletal muscle is a major organ controlling energy metabolism, we investigated whether GLP1 can affect energy metabolism in muscle. We found that treatment of differentiated C2C12 cells with exendin-4 (Ex-4), a GLP1 receptor agonist, reduced oleate: palmitate-induced lipid accumulation and triglyceride content compared with cells without Ex-4 treatment. When we examined the oxygen consumption rate (OCR), not only the basal OCR but also the OCR induced by oleate: palmitate addition was significantly increased in Ex-4-treated differentiated C2C12 cells, and this was inhibited by exendin-9, a GLP1 receptor antagonist. The expression of uncoupling protein 1 (UCP1), beta(3)-adrenergic receptor, peroxisome proliferator-activator receptor a (PPARa) and farnesoid X receptor mRNA was significantly upregulated in Ex-4-treated differentiated C2C12 cells, and the upregulation of these mRNA was abolished by treatment with adenylate cyclase inhibitor (2' 5'-dideoxyadenosine) or PKA inhibitor (H-89). As well, intramuscular injection of Ex-4 into diet-induced obese mice significantly increased the expression of UCP1, PPARa and p-AMPK in muscle. We suggest that exposure to GLP1 increases energy expenditure in muscle through the upregulation of fat oxidation and thermogenic gene expression, which may contribute to reducing obesity and insulin resistance.