Role of Hypothalamic Adgrl1 in Counteracting Hypoglycemia

Abstract The hypothalamus is a hub for counteracting dangerously low blood glucose levels by stimulating the counterregulatory response (CRR) to subsequently restore normal blood glucose levels. We recently identified hypothalamic Adhesion G-protein coupled receptor L 1 (Adgrl1) as a glucose receptor involved in energy and glucose balance. Adgrl1 is necessary in mediating a glucose- inhibited response in the ventromedial nucleus of the hypothalamus (VMH) neurons. Our preliminary findings show that Adgrl1 in the VMH is sufficient to restore the CRR to hypoglycemia in otherwise global Adgrl1 knockout mice. Moreover, Adgrl1 deficiency specifically in the VMH causes an impairment in the glutamate responses to hypoglycemia. Remarkably, Adgrl1 mRNA is decreased in the VMH in mouse models of diabetes, a phenotype that may explain compromised CRR to hypoglycemia. Adgrl1-expressing neurons in the VMH demonstrate impaired neuronal activity following recurrent hypoglycemia. Based on these preliminary data, we hypothesize: Adgrl1 in the VMH is essential for eliciting the counterregulatory response to hypoglycemia and the reduced function of VMH-Adgrl1 contributes to hypoglycemia-associated autonomic failure including compromised glutamatergic tone and impaired sympathoadrenal response. We will test the hypothesis with the following Aims: In Aim1, we will establish the contribution of VMH-Adgrl1 to eliciting the counterregulatory response to hypoglycemia. In Aim2, we will determine the involvement of VMH-Adgrl1 in regulating glutamatergic tone and adrenal sympathetic nerve activity in response to hypoglycemia to explain mechanisms underlying hypoglycemia-associated autonomic failure. Altogether, this project will likely establish the contribution of the novel glucoreceptor Adgrl1 to counteracting hypoglycemia and attenuating hypoglycemia associated autonomic failure.