Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.
Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland; Novo Nordisk A/S, Måløv, Denmark.
Mol Metab. 2022 Jul;61:101479. doi: 10.1016/j.molmet.2022.101479. Epub 2022 Mar 24.
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.
胰高血糖素的分泌可以刺激肝糖产生，这是抵御低血糖的第一道防线。这种反应是由目前尚未完全确定的中枢低血糖感应机制触发的，该机制控制自主神经活动和激素分泌。本研究的目的是确定控制胰岛素诱导胰高血糖素分泌的新的下丘脑基因。
为了获得关于下丘脑低血糖感应机制的新信息，我们结合了胰岛素诱导低血糖反应的遗传和转录组分析，在 BXD 重组近交系小鼠的一组品系中进行。
我们在 8 号染色体和 15 号染色体上发现了两个 QTL。我们进一步研究了 Irak4 和 Cpne8 在 C57BL/6J 和 DBA/2J 小鼠（BXD 小鼠的亲本品系）中的作用，这两个基因都位于 15 号染色体上的 QTL 中。我们发现，DBA/2J 小鼠的胰高血糖素反应较差与 Irak4 的下丘脑表达较高有关，Irak4 编码一种作用于白细胞介素-1 受体（IL-1R）下游的激酶，与 C57BL/6J 小鼠相比，IL-ß 的表达也较高。我们表明，在 DBA/2J 小鼠中脑室内给予 IL-1R 拮抗剂可恢复胰岛素诱导的胰高血糖素分泌；这与下丘脑弓状核和室旁核中 c-fos 表达增加以及自主神经系统两个分支的更高激活有关。然而，全身敲除编码 Ca2+依赖性膜转运和胞吐调节因子的 Cpne8 对胰岛素诱导的胰高血糖素分泌没有影响。
总的来说，我们的数据将 Irak4 确定为控制低血糖激活的下丘脑神经元和胰高血糖素分泌的遗传控制调节剂。
