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

Ken-ichiro Nakajima, Zhenzhong Cui, Chia Li, Jaroslawna Meister, Yinghong Cui, Ou Fu, Adam S. Smith, Shalini Jain, Bradford B. Lowell, Michael J. Krashes and Jürgen Wess ()
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Ken-ichiro Nakajima: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Zhenzhong Cui: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Chia Li: Diabetes Endocrine and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases
Jaroslawna Meister: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Yinghong Cui: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Ou Fu: Graduate School of Agricultural and Life Sciences, The University of Tokyo
Adam S. Smith: Section on Neural Gene Expression, National Institute of Mental Health
Shalini Jain: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Bradford B. Lowell: Beth Israel Deaconess Medical Center, Harvard Medical School
Michael J. Krashes: Diabetes Endocrine and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases
Jürgen Wess: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10268

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