Daily intraparaventricular orexin-A treatment induces weight loss in rats.

The neuropeptide orexin (hypocretin) increases energy expenditure partially through increasing spontaneous physical activity. The ability of exogenous orexin to alter body weight has never been established, however. We sought to determine whether orexin-A microinjected into the paraventricular nucleus of the hypothalamus (PVN) induced weight loss in rats. Chronic guide cannulae were implanted into rats, aimed at the PVN. Rats were given daily microinjections of orexin (0.5 nmol) or vehicle into the PVN for 6 days; food intake and body weight were measured daily. In a separate group of rats, we injected orexin-A and vehicle intra-PVN and measured daily activity levels. Daily orexin treatment induced weight loss: orexin-A-treated rats lost significantly more weight than their vehicle-injected counterparts without a significant difference in food intake. Rats were significantly more active after intra-PVN orexin compared to vehicle. These results support the concept that orexinergic agents have the potential to produce negative energy balance through increasing physical activity. This presents a promising, untapped potential resource for weight loss.