Tmem117 in AVP neurons regulates the counterregulatory response to hypoglycemia

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 investigated 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, an estrus cycle phase-dependent effect 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 AVP production and secretion. Thus, Tmem117 in vasopressin neurons is a physiological regulator of glucagon secretion and highlight the role of these neurons in the coordinated response to hypoglycemia.