Objective To investigate the effects of high-fat diets and rosiglitazone treatment on the expressions of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitofusin-2 (Mfn2) in skeletal muscle of aged rats. Methods Male wistar rats aged 21-23 months were randomly divided into old control group (OC; n=20), high-fat diets group (HF; n=20) and high-fat diets plus rosiglitazone treatment group (RSG; n=20). Male wistar rats aged 4-5 months were selected as young control group (YC; n=20). Insulin sensitivity was evaluated by hyperinsulinemic-euglycemic clamp technique at the end of the 4th and 8th week. The expressions at mRNA and protein levels of PGC-1α and Mfn2 in skeletal muscle were determined by polymerase chain reaction and Western blotting technique. Results (1)After 8 weeks, the levels of free fatty acid [(0. 68±0. 18)mmol/L, (0.82±0. 23) mmol/L and (1. 53±0.40) mmol/L], triglyceride [(0.53±0.13) mmol/L,(0. 63±0. 17) mmol/L and (1.08±0.30) mmol/L]and muscle triglyceride [(1.09±0.17) mmol/L,(1.34±0. 20) mmol/L and (2.07±0. 30) mmol/L]in YC group, OC group and HF group were significantly increased and glucose infusion rate [(30.4±4. 2) mg·kg~(-1)·min~(-1), (20.9±2.2) mg·kg~(-1)·min~(-1) and (12. 0±1.9) mg·kg~(-1)·min~(-1)]was significantly decreased as compared with pre-high fat diet, respectively. The levels of fasting free fatty acid [(0.93±0.29) mmol/L], triglyceride [(0.62±0.12) mmol/L]and music triglyceride [(1.68±0.28) mmol/L]in RSG group were significantly decreased and glucose infusion rate [(16.7±1.7) mg·kg~(-1)·min~(-1)]was significantly higher than in HF group. (2)In skeletal muscle, the expressions at mRNA and protein levels of PGC-1α and Mfn2 decreased in OC group compared with YC group (all P<0.01). The expressions of PGC-1α and Mfn2 were lower significantly in HF group than in OC group, and were higher significantly in RSG group than in HF group (all P<0.01). Conclusions The aged rats fed the high-fat diets develop insulin resistance with decreased expressions of PGC-1α and Mfn2 in skeletal muscle. Insulin sensitivity is improved with rosiglitazone treatment by increasing expressions of PGC-1α and Mfn2 in skeletal muscle.