Type 2 diabetes mellitus (T2DM) is an increasing health issue. Physical activity (PA) in early stages is a preventive measure in the development of degenerative diseases. It has been documented the association between exercise and leptin and adiponectin concentrations. The objective was to evaluate the effect of a physical activity program (PAP) on serum leptin and adiponectin in teenagers with risk factors for developing T2DM. Experimental-longitudinal study. Teenagers (men and women), with T2DM risk factors, aged 14 to 16 years, participated in a PAP for three months, five days a week, 45 minutes each day. Before and after the program, all anthropometric variables, incluiding leptin and adiponectin, were evaluated. 22 adolescents participated in the PAP and they were compared with 22 adolescents from the control group (who did not participate in the PAP). There was a reduction in the serum concentration of leptin in the intervention group (baseline 23 ± 13; after the PAP 14 ± 8, p > 0.0001), compared with the control group (baseline 18 ± 13, three months follow-up 20 ± 14, p < 0.520). Also, the adiponectin concentration increased (baseline 10 ± 3, after the PAP 13 ± 4.0, p > 0.014), compared with the control group (baseline 11 ± 3, 13 ± 4.0 after the PAP p > 0.032). This study support the efficacy of an aerobic exercise intervention on metabolic markers of adolescents with risk factors for developing diabetes.