Objective: The aim of the study was to investigate the effect of weight loss and exercise independently and in combination on circulating levels of adiponectin including low molecular weight, medium molecular weight, and high molecular weight adiponectin and expression of adiponectin and adiponectin receptors (AdipoR) in adipose tissue (AT) and skeletal muscle (SM). Design and Methods: Seventy-nine obese males and females were randomized into the following: 1) exercise only (12 wk of exercise without diet restriction); 2) hypocaloric diet [8 wk of very low energy diet (600 kcal/d) followed by 4 wk with a weight maintenance diet]; and 3) hypocaloric diet and exercise (DEX; 8 wk very low energy diet 800 kcal/d followed by 4 wk weight maintenance diet combined with exercise throughout the 12 wk). Blood samples and biopsies from sc abdominal AT and SM were collected at baseline and after 12 wk. The molecular subforms of adiponectin in serum were determined by Western blot. Results: The mRNA expression of AdipoR1 and -2 in SM was increased significantly in the exercise-only and DEX groups (both P < 0.05). The mRNA expression of adiponectin and AdipoRs in AT was increased significantly in all three groups (all P < 0.01), whereas serum total circulating adiponectin was significantly increased only in the DEX and hypocaloric diet groups (both P < 0.01). All the adiponectin subforms changed in a similar manner as total adiponectin, indicating no specific regulation of any of the subforms by the intervention. Conclusion: Exercise alone and in combination with a diet-induced weight loss enhance the mRNA expression of adiponectin receptors in AT and in SM but only a pronounced hypocaloric-induced weight-loss increases circulating adiponectin in obese subjects.