Functional characterization of the 26RFa/orexin neurons of the lateral hypothalamic area reveals their key role in the control of glucose homeostasis
Defining the nature and molecular mechanisms of the neurocircuitry controlling glucose homeostasis is crucial in understanding how alterations in these pathways promote the development of obesity and type 2 diabetes. Here, we functionally characterize a population of lateral hypothalamic neurons co-expressing the anti-hyperglycemic neuropeptides 26RFa and orexin. Using complementary chemogenetic, pharmacological and genetic approaches, including mice deficient for 26RFa, orexin or both neuropeptides, we investigated the respective contribution of each signaling system to glucose homeostasis. We found that lateral hypothalamic 26RFa neurons extensively co-express orexin, defining a distinct peptidergic population with convergent anti-hyperglycemic properties. Unexpectedly, chemogenetic activation of these neurons potentiated glucose-induced hyperglycemia despite the anti-hyperglycemic properties of both neuropeptides. To understand this paradox, we examined the transcriptional responses of the 26RFa and orexin peptidergic systems and found that neuronal activation was associated with coordinated, glycemic state-dependent downregulation of both signaling systems. Furthermore, genetic loss-of-function approaches revealed distinct contributions of the two neuropeptidergic systems, with orexin signaling mediating most of the metabolic consequences of neuronal activation, whereas 26RFa signaling is required for the dynamic regulation of orexin expression. Finally, our findings provide new insights into the functional organization of lateral hypothalamic 26RFa/orexin neurons and advance our understanding of how coordinated neuropeptidergic signaling contributes to systemic glucose homeostasis.