Journal
MOLECULAR PSYCHIATRY
Volume 23, Issue 5, Pages 1157-1168Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2017.187
Keywords
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Funding
- Swedish Research Council [2014-2945, 2013-7107]
- Novo Nordisk Foundation Excellence project
- Ragnar Soderberg Foundation
- Harald Jeanssons Stiftelse and Greta Jeanssons Stiftelse
- Magnus Bergvalls Stiftelse
- Wallenberg Foundation
- Center for Molecular and Translational Medicine
- National Institute of Health [NIH- DK096139, NIH-DK104897]
- Novo Nordisk Fonden [NNF13OC0003886] Funding Source: researchfish
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Increased motivation for highly rewarding food is a major contributing factor to obesity. Most of the literature focuses on the mesolimbic nuclei as the core of reward behavior regulation. However, the lateral hypothalamus (LH) is also a key reward-control locus in the brain. Here we hypothesize that manipulating glucagon-like peptide-1 receptor (GLP-1R) activity selectively in the LH can profoundly affect food reward behavior, ultimately leading to obesity. Progressive ratio operant responding for sucrose was examined in male and female rats, following GLP-1R activation and pharmacological or genetic GLP-1R blockade in the LH. Ingestive behavior and metabolic parameters, as well as molecular and efferent targets, of the LH GLP-1R activation were also evaluated. Food motivation was reduced by activation of LH GLP-1R. Conversely, acute pharmacological blockade of LH GLP-1R increased food motivation but only in male rats. GLP-1R activation also induced a robust reduction in food intake and body weight. Chronic knockdown of LH GLP-1R induced by intraparenchymal delivery of an adeno-associated virus-short hairpin RNA construct was sufficient to markedly and persistently elevate ingestive behavior and body weight and ultimately resulted in a doubling of fat mass in males and females. Interestingly, increased food reinforcement was again found only in males. Our data identify the LH GLP-1R as an indispensable element of normal food reinforcement, food intake and body weight regulation. These findings also show, for we believe the first time, that brain GLP-1R manipulation can result in a robust and chronic body weight gain. The broader implications of these findings are that the LH differs between females and males in its ability to control motivated and ingestive behaviors.
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