title: Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake.
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.
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Diabetes Endocrine and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Chia
authors.initials: C
authors.lastname: Li
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Jaroslawna
authors.initials: J
authors.lastname: Meister
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 1138657, Japan.
authors.forename: Ou
authors.initials: O
authors.lastname: Fu
authors.affiliation: Section on Neural Gene Expression, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Smith
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jain
authors.affiliation: Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.affiliation: Diabetes Endocrine and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krashes
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004435:Eating / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D007150:Immunohistochemistry; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009478:Neuropeptide Y; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D005680:gamma-Aminobutyric Acid