A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion.
A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion.
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DOI：
10.1016/j.celrep.2016.10.041
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发表时间：
2016-11-08
期刊：
影响因子：
8.8
通讯作者：
Thorens B
中科院分区：
文献类型：
--
作者：
Picard A;Soyer J;Berney X;Tarussio D;Quenneville S;Jan M;Grouzmann E;Burdet F;Ibberson M;Thorens B
对低血糖的反调节反应，即恢复正常的血糖水平，以确保向大脑提供足够的葡萄糖，对生存至关重要。为了发现潜在的大脑调节系统，我们在重组近交系小鼠中进行了基因筛查，寻找控制胰升糖素分泌的数量性状基因座(QTL)，以响应神经性血糖减少症。我们在7号染色体的远端确定了一个QTL，并将这一遗传信息与下丘脑的转录分析相结合。这表明Fgf15是控制胰高血糖素反应的最有力的候选者。下丘脑背内侧及穹隆周围区神经元表达FGF15。侧脑室注射FGF19，人类Fgf15的同源基因，减少由神经糖减少引起的背侧迷走神经复合体神经元和副交感神经的激活，并减少胰高血糖素的分泌。相反，沉默下丘脑背内侧的Fgf15增加了神经糖素减少诱导的胰高血糖素的分泌。这些数据表明，下丘脑Fgf15是胰升糖素分泌的调节器。重组近交系小鼠筛选与胰升糖素分泌相关的QTL结合QTL和转录分析表明下丘脑Fgf15、Fgf15、i.c.V.钝化神经低血糖诱导的迷走神经放电和高血糖素分泌，沉默下丘脑背内侧Fgf15 mRNA，增加高血糖素分泌，对低血糖和反复低血糖的反调节反应缺陷，是胰岛素治疗的糖尿病患者的主要威胁。Picard等人。通过基因筛查和生理学研究，确定下丘脑Fgf15是迄今为止未被怀疑的胰高血糖素分泌调节因子，起到抑制迷走神经活动的作用。
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. Recombinant inbred mice screened for QTLs associated with glucagon secretion Combined QTL and transcriptomic analysis suggests a role for hypothalamic Fgf15 Fgf15 i.c.v. blunts neuroglucopenia-induced vagal nerve firing and glucagon secretion Silencing Fgf15 mRNA in the dorsomedial hypothalamus increases glucagon secretion Defects in the counterregulatory response to hypoglycemia and repeated hypoglycemic episodes are a major threat for insulin-treated diabetic patients. Picard et al. identify hypothalamic Fgf15 as a, so far, unsuspected regulator of glucagon secretion that acts as an inhibitor of vagal activity using a genetic screen and physiological studies.
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影响因子：
7.7
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1152/ajpendo.00332.2001
发表时间：
2002-04-01
影响因子：
5.1
作者：
Burcelin, M;Crivelli, V;Thorens, B
通讯作者：
Thorens, B