The effects of a brain penetrant neurotensin analog, NT-2, on food intake, body weight and activity in the diet induced obese (DIO) mouse.

Abstract

Neurotensin (NT), a brain-gut tridecapeptide, as well as the brain-penetrant NT analog, NT-2, have been shown to elicit a myriad of effects such as hypothermia, analgesia, sedation and suppression of food intake (FI) when administered centrally. These actions are thought to be mediated predominately by NT receptor subtype 1 (NTS1R). The present study examined the effect of NT-2, administered intra-peritoneally (i.p.). DIO mice (50–55 g) were treated with either vehicle or NT-2 (0.3 and 3 mg/kg; i.p.) and FI and activity were recorded continuously (5 min intervals) for 24 h. Overnight body weight (BW) was significantly reduced in NT-2-treated mice by more than 2%, FI was significantly reduced by 72–76% at 6 h, and by 23–31% at 24 h. Moreover, locomotive activities were also transiently reduced. These effects were confirmed in the wild-type mice but not in the NTS1R-deficient mice, supporting the role NTS1R in feeding, weight loss and locomotion. Whether peripheral and/or central activation of NTS1R represent viable approaches to the pharmacotherapy of obesity will require detailed assessment of the relative efficacy and therapeutic index of brain-penetrant and non-brain-penetrant NTS1R agonists.