Mol Metab.: auth.: group Thorens and co-auth.: S.Croizier

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Mol Metab. 2022 Mar 23;101479. doi: 10.1016/j.molmet.2022.101479. 

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

Alexandre Picard 1, Xavier Berney 1, Judit Castillo-Armengol 2, David Tarussio 1, Maxime Jan 1, Ana Rodriguez Sanchez-Archidona 1, Sophie Croizier 1, Bernard Thorens 3

Abstract

Objectives: Glucagon secretion to stimulate hepatic glucose production is a 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 about the mechanisms of hypothalamic hypoglycemia sensing, we combined genetic and transcriptomic analysis of the 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 chromosome 15 QTL, 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 to C57BL/6J mice. We showed that intracerebroventricular administration of an Il-1R antagonist in DBA/2J 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 had, however, 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.

Keywords: autonomous nervous system; genetic screen; glucagon; hypothalamus; insulin-induced hypoglycemia.