Picard Alexandre, Soyer Josselin, Berney Xavier, Tarussio David, Quenneville Simon, Jan Maxime, Grouzmann Eric, Burdet Frédéric, Ibberson Mark, Thorens Bernard
Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
Vital-IT, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
Cell Rep. 2016 Nov 8;17(7):1795-1806. doi: 10.1016/j.celrep.2016.10.041.
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 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, of the parasympathetic nerve, and lowered glucagon secretion. In contrast, silencing Fgf15 in the dorsomedial hypothalamus increased neuroglucopenia-induced glucagon secretion. These data identify hypothalamic Fgf15 as a regulator of glucagon secretion.
对低血糖的对抗调节反应可恢复正常血糖水平，以确保向大脑充分供应葡萄糖，这对生存至关重要。为了发现潜在的大脑调节系统，我们在重组近交小鼠中进行了一项基因筛选，以寻找控制对神经低血糖症作出反应时胰高血糖素分泌的数量性状位点（QTL）。我们在7号染色体远端鉴定出一个QTL，并将这一遗传信息与下丘脑的转录组分析相结合。这揭示Fgf15是控制胰高血糖素反应的最有力候选基因。Fgf15由下丘脑背内侧核和穹窿周区的神经元表达。脑室内注射Fgf15的人类同源物FGF19，可减少神经低血糖症对迷走神经背侧复合体神经元、副交感神经的激活，并降低胰高血糖素分泌。相反，在下丘脑背内侧核中沉默Fgf15会增加神经低血糖症诱导的胰高血糖素分泌。这些数据确定下丘脑Fgf15是胰高血糖素分泌的调节因子。
