Introduction: The effectiveness of various extrinsic and intrinsic regulatory signals on food intake and body weight can be influenced by hypothalamic neuropeptide-Y (NPY) and proopiomelanocortin (POMC) neurons. While several studies emphasize the vital role of regular physical activity in effective weight management, how these molecular and cellular processes interact with physical activity remains an area in need of further exploration. Hence, this study aims to investigate the impact of various long-term physical activities intensities on the regulation of body weight and appetite. Methods: Twenty-one Wistar rats (n=7) were randomized into three groups: 1) Control group, 2) a group engaged in regular exercise at moderate intensity for 24 weeks (24-ME, 5 days each week), and 3) a group frequently and intensively exercising over 24 weeks (24-IE, 5 days each week). Subsequently, Reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) methods were performed to measure gene expression of hypothalamic arcuate nucleus NPY and POMC, as well as serum levels of acyl-ghrelin and leptin. Results: The POMC mRNA level decreased in the 24-ME group compared to the control rats. However, intensive regular exercise increased NPY expression compared to the control rats. Inversely, body weight and food intake levels were considerably higher in the 24-ME and 24-IE groups than in the control group. Different intensities of prolonged exercise seem to heighten appetite, eventually increasing body weight through distinct molecular pathways. Conclusion: Hence, it can be concluded that prolonged intensive exercise may not be a practical approach for weight loss.