Hypothalamic Irak4 is a genetically controlled regulator of hypoglycemia-induced glucagon secretion.

Animals Glucagon / metabolism Hypoglycemia / genetics Hypothalamus / metabolism Insulin / metabolism Interleukin-1 Receptor-Associated Kinases Mice Mice, Inbred C57BL Mice, Inbred DBA
Autonomous nervous system Genetic screening Glucagon Hypothalamus Insulin-induced hypoglycemia

Journal

Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730

Informations de publication

Date de publication:
07 2022
Historique:
received: 14 02 2022
revised: 16 03 2022
accepted: 17 03 2022
pubmed: 28 3 2022
medline: 9 6 2022
entrez: 27 3 2022
Statut: ppublish

Résumé

Glucagon secretion to stimulate hepatic glucose production is the first line of defense against hypoglycemia. This response is triggered by so far incompletely characterized central hypoglycemia-sensing mechanisms, which control autonomous nervous activity and hormone secretion. The objective of this study was to identify novel hypothalamic genes controlling insulin-induced glucagon secretion. To obtain new information on the mechanisms of hypothalamic hypoglycemia sensing, we combined genetic and transcriptomic analysis of glucagon response to insulin-induced hypoglycemia in a panel of BXD recombinant inbred mice. We identified two QTLs on chromosome 8 and chromosome 15. We further investigated the role of Irak4 and Cpne8, both located in the QTL on chromosome 15, in C57BL/6J and DBA/2J mice, the BXD mouse parental strains. We found that the poor glucagon response of DBA/2J mice was associated with higher hypothalamic expression of Irak4, which encodes a kinase acting downstream of the interleukin-1 receptor (Il-1R), and of Il-ß when compared with C57BL/6J mice. We showed that intracerebroventricular administration of an Il-1R antagonist in DBA/2J mice restored insulin-induced glucagon secretion; this was associated with increased c-fos expression in the arcuate and paraventricular nuclei of the hypothalamus and with higher activation of both branches of the autonomous nervous system. Whole body inactivation of Cpne8, which encodes a Ca Collectively, our data identify Irak4 as a genetically controlled regulator of hypoglycemia-activated hypothalamic neurons and glucagon secretion.

Identifiants

DOI: 10.1016/j.molmet.2022.101479 PMID: 35339728 PMC: PMC9046887
pubmed: 35339728
pii: S2212-8778(22)00048-5
doi: 10.1016/j.molmet.2022.101479
pmc: PMC9046887
pii:
doi:

Substances chimiques

Insulin 0
Glucagon 9007-92-5
Interleukin-1 Receptor-Associated Kinases EC 2.7.11.1
Irak4 protein, mouse EC 2.7.11.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

101479

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.

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Auteurs

Alexandre Picard (A)

Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.

Xavier Berney (X)

Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.

Judit Castillo-Armengol (J)

Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland; Novo Nordisk A/S, Måløv, Denmark.

David Tarussio (D)

Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.

Maxime Jan (M)

Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.

Ana Rodriguez Sanchez-Archidona (AR)

Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.

Sophie Croizier (S)

Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.

Bernard Thorens (B)

Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland. Electronic address: bernard.thorens@unil.ch.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Hypothalamic Irak4 is a genetically controlled...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Hormones peptidiques › Hormones pancréatiques › Glucagon › Hypothalamic Irak4 is a genetically controlled...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles du métabolisme du glucose › Hypoglycémie › Hypothalamic Irak4 is a genetically controlled...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Diencéphale › Hypothalamus › Hypothalamic Irak4 is a genetically controlled...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Hormones peptidiques › Hormones pancréatiques › Insulines › Insuline › Hypothalamic Irak4 is a genetically controlled...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Interleukin-1 Receptor-Associated Kinases › Hypothalamic Irak4 is a genetically controlled...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Hypothalamic Irak4 is a genetically controlled...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Hypothalamic Irak4 is a genetically controlled...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée DBA › Hypothalamic Irak4 is a genetically controlled...