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

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⁺⁺-dependent regulator of membrane trafficking and exocytosis, however, had no impact on insulin-induced glucagon secretion. Collectively, our data identify Irak4 as a genetically controlled regulator of hypoglycemia-activated hypothalamic neurons and glucagon secretion. • A genetic screening in mice for hypoglycemia-induced glucagon secretion yielded two QTLs. • Hypothalamic Irak4 was identified as a candidate regulator of glucagon secretion. • High arcuate Irak4 expression in DBA/2J mice correlated with low glucagon secretion. • Inhibition of central Il-1β/Irak4 signaling in DAB/2J mice restored glucagon secretion. [ABSTRACT FROM AUTHOR]