PURPOSE: A high-fructose diet is supposed to induce the so-called metabolic syndrome, associated with increased fat deposition in adipose tissue. Physical exercise may counteract the induction of the metabolic syndrome. The present study aims to investigate the effect of voluntary physical activity (VPA) on cGMP-mediated lipolysis in retroperitoneal adipose tissue in a metabolic syndrome model induced in rats by a high-fructose diet. METHODS: Male Sprague-Dawley rats in control and fructose (F) groups had free access to either plain drinking water or a solution of 20% D-fructose, combined with a standard diet for 8 wk. Rats in the fructose + activity (F + A) group performed voluntary physical activity with a running wheel. Blood pressure, serum glucose, lipids and natriuretic peptide levels were measured on the last day of the feeding period. In retroperitoneal adipose tissue, cGMP, hormone-sensitive lipase (HSL), perilipin-1, aquaglyceroporin levels, and adipocyte diameter were analyzed. RESULTS: Systolic blood pressure, glucose, and triacylglycerol were higher in the F groups compared to the control. The C-type natriuretic peptide was higher in the F group compared to the control. The cGMP level in retroperitoneal adipose tissue was higher in the F + A group than F group. Higher HSL and perilipin-1 levels were observed in the F + A group compared to the F and control groups. Adipocyte diameter was lower in the F + A group compared to the F group. CONCLUSION: Regular physical exercise triggers lipolytic effects in adipose tissue through cGMP, HSL, and perilipin-1-mediated pathway in fructose-induced metabolic syndrome model in rats, preventing the increase in adipocyte diameter.