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Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice.

التفاصيل البيبلوغرافية
العنوان: Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice.
المؤلفون: Lewis JE; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK. Electronic address: jl2033@medschl.cam.ac.uk., Woodward OR; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK., Nuzzaci D; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK., Smith CA; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK., Adriaenssens AE; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK., Billing L; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK., Brighton C; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK., Phillips BU; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK., Tadross JA; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK; Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK., Kinston SJ; Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Ciabatti E; Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Göttgens B; Department of Haematology, Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK., Tripodi M; MRC Laboratory of Molecular Biology, Neurobiology Division, Francis Crick Avenue, Cambridge CB2 0QH, UK., Hornigold D; Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca Ltd, Cambridge, UK., Baker D; Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca Ltd, Cambridge, UK., Gribble FM; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK. Electronic address: fmg23@cam.ac.uk., Reimann F; Wellcome Trust - MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK. Electronic address: fr222@cam.ac.uk.
المصدر: Molecular metabolism [Mol Metab] 2022 Dec; Vol. 66, pp. 101604. Date of Electronic Publication: 2022 Sep 30.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Elsevier GmbH Country of Publication: Germany NLM ID: 101605730 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2212-8778 (Electronic) Linking ISSN: 22128778 NLM ISO Abbreviation: Mol Metab Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [München] : Elsevier GmbH, 2012-
مواضيع طبية MeSH: Eating* , Neurons*/metabolism , Receptors, G-Protein-Coupled*/metabolism, Animals ; Mice ; Hypothalamus/cytology ; Hypothalamus/metabolism
مستخلص: Objective: Insulin-like peptide 5 (INSL5) signalling, through its cognate receptor relaxin/insulin-like family peptide receptor 4 (RXFP4), has been reported to be orexigenic, and the high fat diet (HFD) preference observed in wildtype mice is altered in Rxfp4 knock-out mice. In this study, we used a new Rxfp4-Cre mouse model to investigate the mechanisms underlying these observations.
Methods: We generated transgenic Rxfp4-Cre mice and investigated central expression of Rxfp4 by RT-qPCR, RNAscope and intraparenchymal infusion of INSL5. Rxfp4-expressing cells were chemogenetically manipulated in global Cre-reporter mice using designer receptors exclusively activated by designer drugs (DREADDs) or after stereotactic injection of a Cre-dependent AAV-DIO-Dq-DREADD targeting a population located in the ventromedial hypothalamus (RXFP4 VMH ). Food intake and feeding motivation were assessed in the presence and absence of a DREADD agonist. Rxfp4-expressing cells in the hypothalamus were characterised by single-cell RNA-sequencing (scRNAseq) and the connectivity of RXFP4 VMH cells was investigated using viral tracing.
Results: Rxfp4-Cre mice displayed Cre-reporter expression in the hypothalamus. Active expression of Rxfp4 in the adult mouse brain was confirmed by RT-qPCR and RNAscope. Functional receptor expression was supported by cyclic AMP-responses to INSL5 application in ex vivo brain slices and increased HFD and highly palatable liquid meal (HPM), but not chow, intake after intra-VMH INSL5 infusion. scRNAseq of hypothalamic RXFP4 neurons defined a cluster expressing VMH markers, alongside known appetite-modulating neuropeptide receptors (Mc4r, Cckar and Nmur2). Viral tracing demonstrated RXFP4 VMH neural projections to nuclei implicated in hedonic feeding behaviour. Whole body chemogenetic inhibition (Di-DREADD) of Rxfp4-expressing cells, mimicking physiological INSL5-RXFP4 Gi-signalling, increased intake of the HFD and HPM, but not chow, whilst activation (Dq-DREADD), either at whole body level or specifically within the VMH, reduced HFD and HPM intake and motivation to work for the HPM.
Conclusion: These findings identify RXFP4 VMH neurons as regulators of food intake and preference, and hypothalamic RXFP4 signalling as a target for feeding behaviour manipulation.
(Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)
معلومات مُعتمدة: MC_PC_17230 United Kingdom MRC_ Medical Research Council; United Kingdom BB_ Biotechnology and Biological Sciences Research Council; 220271/Z/20/Z United Kingdom WT_ Wellcome Trust; CL-2019-14-504 United Kingdom DH_ Department of Health; 100574/Z/12/Z United Kingdom WT_ Wellcome Trust; MC_UU_00014/5 United Kingdom MRC_ Medical Research Council; MC_UU_12012/5 United Kingdom MRC_ Medical Research Council; MC_UU_12012/3 United Kingdom MRC_ Medical Research Council; MC_UU_00014/3 United Kingdom MRC_ Medical Research Council; MC_UP_1201/2 United Kingdom MRC_ Medical Research Council; MRC_MC_UU_12012/5 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust; MRC_MC_UU_12012/3 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة: Keywords: CNS; Food intake; Insl5; RXFP4; VMH
المشرفين على المادة: 0 (Receptors, G-Protein-Coupled)
0 (RXFP4 protein, mouse)
تواريخ الأحداث: Date Created: 20221002 Date Completed: 20221227 Latest Revision: 20240731
رمز التحديث: 20240731
مُعرف محوري في PubMed: PMC9579047
DOI: 10.1016/j.molmet.2022.101604
PMID: 36184065
قاعدة البيانات: MEDLINE
الوصف
تدمد:2212-8778
DOI:10.1016/j.molmet.2022.101604