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

• DOI: 10.1016/j.molmet.2022.101479
• Publication Date: 2022-03-24T01:37:14Z
• Authors: Alexandre Picard; Xavier Berney; Judit Castillo-Ar...; David Tarussio; Maxime Jan; Ana Rodriguez San...; Sophie Croizier; Bernard Thorens
• Keywords: Genetically engineered

Glucagon secretion to stimulate hepatic glucose production is the first line of defense against hypoglycemia. This response triggered by so far incompletely characterized central hypoglycemia-sensing mechanisms, which control autonomous nervous activity and hormone secretion. The objective this study was identify novel hypothalamic genes controlling insulin-induced glucagon To obtain new information on mechanisms hypoglycemia sensing, we combined genetic transcriptomic analysis in a panel BXD recombinant inbred mice. We identified two QTLs chromosome 8 15. further investigated role Irak4 Cpne8, both located QTL 15, C57BL/6J DBA/2J mice, mouse parental strains. found that poor mice associated with higher expression Irak4, encodes kinase acting downstream interleukin-1 receptor (Il-1R), Il-ß when compared showed intracerebroventricular administration an Il-1R antagonist restored secretion; increased c-fos arcuate paraventricular nuclei hypothalamus activation branches system. Whole body inactivation Ca++-dependent regulator membrane trafficking exocytosis, however, had no impact Collectively, our data as genetically controlled hypoglycemia-activated neurons