Elsevier

Molecular Metabolism

Volume 2, Issue 4, November 2013, Pages 423-434
Molecular Metabolism

Original article
Loss of neurotensin receptor-1 disrupts the control of the mesolimbic dopamine system by leptin and promotes hedonic feeding and obesity

https://doi.org/10.1016/j.molmet.2013.07.008Get rights and content
Under a Creative Commons license
open access

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; LepRbNts 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.

Abbreviations

LHA
lateral hypothalamic area
DA
dopamine
LepRb
long form of the leptin receptor
Nts
neurotensin
NtsR1
neurotensin receptor-1
NtsR2
neurotensin receptor-2
NtsR1KO
neurotensin receptor-1 knock out
VTA
ventral tegmental area
SN
substantia nigra
TH
tyrosine hydroxylase
NAc
nucleus accumbens
OX
Orexin/hypocretin
MCH
melanin concentrating hormone
pSTAT3
phosphorylation of signal transducer and activator of transcription 3
PD
palatable diet

Keywords

Neurotensin
Obesity
Orexin
Dopamine

Cited by (0)

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.