AUTHOR COPY ONLY a-MSH overexpression in the nucleus tractus solitarius decreases fat mass and elevates heart rate

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 a-MSH in the nucleus tractus solitarius (NTS) of the brain stem. The a-MSH vector (LVi‐a-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‐a-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‐a-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‐a-MSH‐EGFP treatment reduced urine secretion. Thus, the results demonstrate that long-term a-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 a-MSH-induced long-term effects on adiposity and in regulation of sympathetic and parasympathetic activities.