Introduction: Compared to other adipose tissues, Subcutaneous Adipose Tissue (SAT), may have different effects on health and insulin resistance. The purpose of this study was to investigate the effect of aerobic exercise on serum orexin-A (OXA), SAT thermogenic indices gene expression, and insulin resistance in high-fat diet-induced obese rats. Materials and Methods: Thirty-two male wistar rats with an average weight of 180-200 g were randomly assigned into 4 equal groups: normal fat diet (NFD), high-fat diet-induced obesity (HFDO), normal fat diet after high-fat dietinduced obesity (HFDO-NFD) and the aerobic exercise group with normal fat diet after high-fat dietinduced obesity (HFDO-AEX). After induction of obesity in the HFDO group and 48 hours after eight weeks of aerobic exercise in other groups (60% of maximum exercise capacity), fasting levels of serum OXA, FBS, insulin resistance, lipid profiles, and gene expression of PGC-1 and UCP1 in SAT were measured. Results: Results showed that, following HFD, compared to the NFD group, levels of OXA, HDL-C, PGC-1 and UCP1 gene expression in the HFDO group, significantly decreased, and lipid profiles, Lee index, FBS, insulin and insulin resistance significantly increased (P<0. 01). Also after aerobic exercise in the HFDO-AEX group, compared to the HFDO group, levels of OXA (34. 74%), HDL-C (23. 65%), PGC-1 and UCP1 genes expression (77. 38% and 78. 72%, respectively) increased and values of lipid profile, Lee index (18. 34%), FBS (32. 28%), insulin (4. 01%) and insulin resistance (37. 48%) were significantly decreased (P! 0. 001), changes however, not significant in the HFDO-NFD group. Conclusion: Data obtained suggest that aerobic exercise by an increase in the OXA and alteration in the SAT thermogenic gene expression indices may improve insulin resistance and blood lipid profiles.