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Hypothalamic Irak4 is a genetically controlled regulator of hypoglycemia-induced glucagon secretion.
- Source :
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Molecular metabolism [Mol Metab] 2022 Jul; Vol. 61, pp. 101479. Date of Electronic Publication: 2022 Mar 24. - Publication Year :
- 2022
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Abstract
- 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.<br />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.<br />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 <superscript>++</superscript> -dependent regulator of membrane trafficking and exocytosis, however, had no impact on insulin-induced glucagon secretion.<br />Conclusions: Collectively, our data identify Irak4 as a genetically controlled regulator of hypoglycemia-activated hypothalamic neurons and glucagon secretion.<br /> (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 2212-8778
- Volume :
- 61
- Database :
- MEDLINE
- Journal :
- Molecular metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 35339728
- Full Text :
- https://doi.org/10.1016/j.molmet.2022.101479