α-MSH overexpression in the nucleus tractus solitarius decreases fat mass and elevates heart rate

Abstract

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.

Alpha–Melanocyte-stimulating Hormone Induces Vasodilation and Exerts Cardioprotection Through the Heme-Oxygenase Pathway in Rat Hearts

“…Such HR-elevating effects of α-MSH have been confirmed on other animal models. 19,20 The contribution of HO-1 activity to this effect was demonstrated by the observation that increased HR stimulated by the hormone was counteracted by SnPP, an inhibitor of HO-1. Nevertheless, it should be noted that the conspicuous low HRs in the SnPP + MSH group are partly due to the observed many severe arrhythmic events, as described in this report.…”

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

“…Some studies have found a reduced blood pressure and heart rate following micro-injection of α-MSH or a synthetic agonist into the NTS of anesthetized, spontaneously hypertensive rats and normotensive Sprague-Dawley rats [168, 169]. On the other hand, an α-MSH-expressing viral vector injected into the NTS increased sympathetic activity and the heart rate and reduced parasympathetic activity in mice [170]. Similarly, Iwasa et al [171] observed an increased heart rate after α-MSH had been microinjected into the IML, the location of cholinergic sympathetic preganglionic neurons.…”

Hypothalamic γ-melanocyte stimulating hormone gene delivery reduces fat mass in male mice

“…Our previous work highlighted the importance of α-MSH in the anti-obesity effects as we showed that chronic lentiviral α-Msh overexpression in the ARC in diet-induced obese (DIO) mice can reduce weight gain and adiposity without affecting FI (Eerola et al 2013). Furthermore, by inducing a 1.3-fold increase in α-MSH in the NTS using the same system, we observed a significant FI-and weight-independent improvement in fat mass (FM) (Eerola et al 2014). The aim of the current work was to assess the long-term metabolic effects of local γ-Msh overexpression alone in the hypothalamus and to test whether the composition of diet plays an impact on the physiological effects.…”