Camitine induces autophagy and restores high-fat diet-induced mitochondrial dysfunction

Objective. Autophagy is suppressed in skeletal muscle and the liver with insulin resistance induced by a high-fat diet. Autophagy is essential for maintaining mitochondrial function, and dysfunctional mitochondria are associated with insulin resistance. As camitine treatment is well known to improve insulin resistance by promoting mitochondrial function, we investigated if camitine affects autophagy in the skeletal muscle of a high-fat diet-induced rodent model of obesity. Results. After 6 weeks on a high-fat diet (48 kcal% fat), mice developed glucose intolerance, and the gastrocnemius muscle showed a decrease in insulin signaling and mitochondrial function, which was reversed after camitine (100 mg/kg/day) treatment by oral gavage for 2 weeks. Swollen mitochondria with destroyed cristae were observed in the skeletal muscle of high-fat diet-fed mice but were not there after camitine treatment. High fat diet decreased LC3B-II, a marker of autophagosome formation, and increased sequestosome 1 (SQSTM1), expression of which was reversed after camitine treatment. In C2C12 myotubes, prolonged treatment with palmitate suppressed autophagy, which was relieved by camitine treatment. However, the induction of autophagy by camitine in C2C12 myotubes was not observed after knock-down of peroxisome proliferator-activated receptor gamma (PPAR gamma), which is known to regulate autophagy. Conclusion. We conclude that the removal of dysfunctional mitochondria by induction of autophagy through PPAR gamma may be a novel mechanism by which camitine improves insulin resistance and mitochondrial dysfunction in obesity. (C) 2017 Elsevier Inc. All rights reserved.