title: Loss of neurotensin receptor-1 disrupts the control of the mesolimbic dopamine system by leptin and promotes hedonic feeding and obesity.
abstract: Neurons of the lateral hypothalamic area (LHA) control motivated behaviors such as feeding and ambulatory activity, in part by modulating mesolimbic dopamine (DA) circuits. The hormone, leptin, acts via the long form of the leptin receptor (LepRb) in the brain to signal the repletion of body energy stores, thereby decreasing feeding and promoting activity. LHA LepRb neurons, most of which contain neurotensin (Nts; LepRb(Nts) neurons) link leptin action to the control of mesolimbic DA function and energy balance. To understand potential roles for Nts in these processes, we examined mice null for Nts receptor 1 (NtsR1KO). While NtsR1KO mice consume less food than controls on a chow diet, they eat more and become obese when fed a high-fat, high-sucrose palatable diet; NtsR1KO mice also exhibit augmented sucrose preference, consistent with increased hedonic feeding in these animals. We thus sought to understand potential roles for NtsR1 in the control of the mesolimbic DA system and LHA leptin action. LHA Nts cells project to DA-containing midbrain areas, including the ventral tegmental area (VTA) and the substantia nigra (SN), where many DA neurons express NtsR1. Furthermore, in contrast to wild-type mice, intra-LHA leptin treatment increased feeding and decreased VTA Th expression in NtsR1KO mice, consistent with a role for NtsR1 signaling from LHA LepRb neurons in the suppression of food intake and control of mesolimbic DA function. Additionally, these data suggest that other leptin-regulated LHA neurotransmitters normally oppose aspects of Nts action to promote balanced responses to leptin.
authors: Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Darren
authors: D
authors: Opland
authors: Amy
authors: A
authors: Sutton
authors: Hillary
authors: H
authors: Woodworth
authors: Juliette
authors: J
authors: Brown
authors: Raluca
authors: R
authors: Bugescu
authors: Adriana
authors: A
authors: Garcia
authors: Lyndsay
authors: L
authors: Christensen
authors: Christopher
authors: C
authors: Rhodes
authors: Martin
authors: M
authors: Myers
authors: Gina
authors: G
authors: Leinninger
keywords: DA, dopamine; Dopamine; LHA, lateral hypothalamic area; LepRb, long form of the leptin receptor; MCH, melanin concentrating hormone; NAc, nucleus accumbens; Neurotensin; Nts, neurotensin; NtsR1, neurotensin receptor-1; NtsR1KO, neurotensin receptor-1 knock out; NtsR2, neurotensin receptor-2; OX, Orexin/hypocretin; Obesity; Orexin; PD, palatable diet; SN, substantia nigra; TH, tyrosine hydroxylase; VTA, ventral tegmental area; pSTAT3, phosphorylation of signal transducer and activator of transcription 3