The POMC pathway is involved in the regulation of energy and cardiovascular homeostasis in the hypothalamus and the brain stem. Although the acute effects of POMC-derived peptides in different brain locations have been elucidated, the chronic site-specific effects of distinct peptides remain to be studied. To this end, we used a lentiviral gene delivery vector to study the long-term effects of α-MSH in the nucleus tractus solitarius (NTS) of the brain stem. The α-MSH vector (LVi-α-MSH-EGFP) based on the N-terminal POMC sequence and a control vector (LVi-EGFP) were delivered into the NTS of C57BL/6N male mice fed on a western diet. Effects on body weight and composition, feeding, glucose metabolism, and hemodynamics by telemetric analyses were studied during the 12-week follow-up. The LVi-α-MSH-EGFP-treated mice had a significantly smaller gain in the fat mass compared with LVi-EGFP-injected mice. There was a small initial decrease in food intake and no differences in the physical activity. Glucose metabolism was not changed compared with the control. LVi-α-MSH-EGFP increased the heart rate (HR), which was attenuated by adrenergic blockade suggesting an increased sympathetic activity. Reduced response to muscarinic blockade suggested a decreased parasympathetic activity. Fitting with sympathetic activation, LVi-α-MSH-EGFP treatment reduced urine secretion. Thus, the results demonstrate that long-term α-MSH overexpression in the NTS attenuates diet-induced obesity. Modulation of autonomic nervous system tone increased the HR and most probably contributed to an anti-obesity effect. The results underline the key role of NTS in the α-MSH-induced long-term effects on adiposity and in regulation of sympathetic and parasympathetic activities.