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

OBJECTIVES: 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 obje...

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Detalles Bibliográficos
Autores principales: Picard, Alexandre, Berney, Xavier, Castillo-Armengol, Judit, Tarussio, David, Jan, Maxime, Sanchez-Archidona, Ana Rodriguez, Croizier, Sophie, Thorens, Bernard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9046887/
https://www.ncbi.nlm.nih.gov/pubmed/35339728
http://dx.doi.org/10.1016/j.molmet.2022.101479
Descripción
Sumario:OBJECTIVES: 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. METHODS: 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. RESULTS: 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(++)-dependent regulator of membrane trafficking and exocytosis, however, had no impact on insulin-induced glucagon secretion. CONCLUSIONS: Collectively, our data identify Irak4 as a genetically controlled regulator of hypoglycemia-activated hypothalamic neurons and glucagon secretion.