Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
EMBO Rep. 2023 Aug 3;24(8):e57344. doi: 10.15252/embr.202357344. Epub 2023 Jun 14.
The counterregulatory response to hypoglycemia (CRR), which ensures a sufficient glucose supply to the brain, is an essential survival function. It is orchestrated by incompletely characterized glucose-sensing neurons, which trigger a coordinated autonomous and hormonal response that restores normoglycemia. Here, we investigate the role of hypothalamic Tmem117, identified in a genetic screen as a regulator of CRR. We show that Tmem117 is expressed in vasopressin magnocellular neurons of the hypothalamus. Tmem117 inactivation in these neurons increases hypoglycemia-induced vasopressin secretion leading to higher glucagon secretion in male mice, and this effect is estrus cycle phase dependent in female mice. Ex vivo electrophysiological analysis, in situ hybridization, and in vivo calcium imaging reveal that Tmem117 inactivation does not affect the glucose-sensing properties of vasopressin neurons but increases ER stress, ROS production, and intracellular calcium levels accompanied by increased vasopressin production and secretion. Thus, Tmem117 in vasopressin neurons is a physiological regulator of glucagon secretion, which highlights the role of these neurons in the coordinated response to hypoglycemia.
低血糖的代偿反应（CRR）是确保大脑获得足够葡萄糖供应的重要生存功能，它由尚未完全确定的葡萄糖感应神经元来调控。这些神经元会引发协调的自主和激素反应，使血糖恢复正常。在此，我们研究了下丘脑 Tmem117 在 CRR 中的作用，该基因是通过遗传筛选确定的调节因子。我们发现 Tmem117 在位于下丘脑的血管加压素大细胞神经元中表达。这些神经元中的 Tmem117 失活会增加低血糖诱导的血管加压素分泌，导致雄性小鼠中胰高血糖素分泌增加，而在雌性小鼠中，这种作用与动情周期阶段有关。离体电生理分析、原位杂交和体内钙成像显示，Tmem117 失活不会影响血管加压素神经元的葡萄糖感应特性，但会增加内质网应激、ROS 产生和细胞内钙水平，同时增加血管加压素的产生和分泌。因此，血管加压素神经元中的 Tmem117 是胰高血糖素分泌的生理性调节因子，这突显了这些神经元在低血糖协调反应中的作用。
