A genetic screen identifies hypothalamic Fgf15/19 as a regulator of glucagon secretion

The counterregulatory response to hypoglycemia, which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain, is critical for survival. To discover underlying brain regulatory systems, we performed a genetic screen in recombinant inbred mice for quantitative trait loci (QTL) controlling glucagon secretion in response to neuroglucopenia. We identified a QTL on the distal part of chromosome 7 and combined this genetic information with transcriptomic analysis of hypothalami. This revealed Fgf15 as the strongest candidate to control the glucagon response. Fgf15 was found to be expressed by neurons of the dorsomedial hypothalamus and the perifornical area. Intracerebroventricular injection of FGF19, the human ortholog of Fgf15, reduced activation by neuroglucopenia of dorsal vagal complex neurons and of the parasympathetic nerve, leading to a lower glucagon secretion. These data show that Fgf15 in hypothalamic neurons is a regulator of vagal nerve activity in response to neuroglucopenia. 36 BXD strains + 4 parental strains, 1 time point, basal condition without treatment低血糖反调节反应（counterregulatory response to hypoglycemia）可恢复正常血糖水平，确保大脑获得充足的葡萄糖供给，对生物体存活至关重要。为揭示潜在的大脑调节系统，我们在重组近交系小鼠（recombinant inbred mice）中开展数量性状位点（quantitative trait loci，QTL）筛选，以探究神经低血糖症（neuroglucopenia）刺激下的胰高血糖素分泌（glucagon secretion）调控机制。我们在7号染色体远端区域定位到一个QTL，并将该遗传信息与下丘脑转录组分析（transcriptomic analysis of hypothalami）相结合，最终鉴定出成纤维细胞生长因子15（Fgf15）为调控胰高血糖素应答的最强候选基因。研究发现，Fgf15由下丘脑背内侧核（dorsomedial hypothalamus）与穹窿周区（perifornical area）的神经元表达。向小鼠脑室内注射（intracerebroventricular injection）成纤维细胞生长因子19（FGF19，Fgf15的人类同源基因（human ortholog））可减弱神经低血糖症诱导的迷走神经背核复合体（dorsal vagal complex）神经元及副交感神经（parasympathetic nerve）激活，进而降低胰高血糖素分泌。上述数据表明，下丘脑神经元中的Fgf15是神经低血糖症应答过程中迷走神经活动（vagal nerve activity）的调控因子。本实验采用36个BXD品系（BXD strains）与4个亲本品系（parental strains），仅设置1个时间点，使用未施加任何处理的基础实验条件。