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Nat Commun. 2016 Jan 8;7:10268. doi: 10.1038/ncomms10268.

Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake.

Author information

1
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
2
Diabetes Endocrine and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
3
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 1138657, Japan.
4
Section on Neural Gene Expression, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
5
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

Agouti-related peptide (AgRP) neurons of the hypothalamus play a key role in regulating food intake and body weight, by releasing three different orexigenic molecules: AgRP; GABA; and neuropeptide Y. AgRP neurons express various G protein-coupled receptors (GPCRs) with different coupling properties, including Gs-linked GPCRs. At present, the potential role of Gs-coupled GPCRs in regulating the activity of AgRP neurons remains unknown. Here we show that the activation of Gs-coupled receptors expressed by AgRP neurons leads to a robust and sustained increase in food intake. We also provide detailed mechanistic data linking the stimulation of this class of receptors to the observed feeding phenotype. Moreover, we show that this pathway is clearly distinct from other GPCR signalling cascades that are operative in AgRP neurons. Our data suggest that drugs able to inhibit this signalling pathway may become useful for the treatment of obesity.

PMID:
26743492
PMCID:
PMC4729878
DOI:
10.1038/ncomms10268
[Indexed for MEDLINE]
Free PMC Article

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