Insulin potentiates leptin effects on muscle accrual and glucose homeostasis. However, the relationship between leptin's central effects on peripheral insulin sensitivity and the associated structural changes remain unclear. We hypothesized that central leptin infusion modifies muscle size through activation of insulin signaling. Muscle insulin signaling, enzymes of fatty acid metabolism, mitochondrial respiratory chain complexes, proliferating cell nuclear antigen (PCNA) and fiber area were analyzed in the gastrocnemius of chronic central infused (L), pair-fed (PF) and control rats. PCNA-positive nuclei, fiber area, GLUT4 and glycogen levels and activation of Akt and mechanistic target of rapamycin were increased in L with no changes in PF. Acetyl-CoA carboxylase-beta mRNA levels and non-esterified fatty acid and triglyceride content were reduced and carnitine palmitoyltransferase-lb expression and mitochondrial complexes augmented in L These results suggest that leptin promotes an increase in muscle size associated with improved insulin signaling favored by lipid profile. (C) 2017 Elsevier B.V. All rights reserved.