Introduction: With increasing weight, the risk of developing various heart diseases increases. Although exercise is effective in controlling obesity, and the molecular mechanism of this effect is not well known. This study aims to identify, rank and analyse changes in the expression of key proteins in overweight individuals after aerobic exercise training. Materials and Methods: Transformed proteins expressed in skeletal muscle of overweight adolescents were analyzed in a protein-protein interaction network, using Cytoscape software. Key elements of the interactome and the biological processes associated with protein clusters were identified and analyzed. Results: Seven key genes and two important gene clusters related to the network were introduced. The elements of the first cluster were related to 30 important biological processes that control sugar and nucleotide metabolism. The NAD metabolic process was introduced as the most important biological process. Conclusion: Expression of seven key genes with various impacts is altered in overweight adolescents. The PKM gene, as the key gene, plays an important role in the activation of pyruvate. PGK1 was identified and introduced via the network analysis. Considering the importance of each of the seven genes identified and the related processes, the feasibility and ground work for possible drug treatment can be facilitated.