Synaptic Interaction between Hypocretin (Orexin) and Neuropeptide Y Cells in the Rodent and Primate Hypothalamus: A Novel Circuit Implicated in Metabolic and Endocrine Regulations

TLDR

Hypocretin neurons in the lateral hypothalamus synapse onto arcuate nucleus NPY neurons that also express leptin receptors, suggesting a circuit where hypocretin excitation could raise NPY release and feeding while leptin and NPY provide opposing regulatory signals. The study aimed to test whether hypocretin modulates metabolic and endocrine functions through synaptic regulation of the NPY system in rats and primates. The authors examined hypothalamic circuitry in rat and primate brains, focusing on synaptic interactions between hypocretin terminals and NPY neurons. The data show that hypocretin, leptin, and NPY interact directly in the hypothalamus, with hypocretin injection increasing feeding, supporting a role for this circuit in metabolic and endocrine regulation across species.

Abstract

Hypocretin (orexin) has recently been shown to increase feeding when injected into the brain. Using both rat and primate brains, we tested the hypothesis that a mechanism of hypocretin action might be related to synaptic regulation of the neuropeptide Y (NPY) system. Hypocretin-immunoreactive terminals originating from the lateral hypothalamus make direct synaptic contact with neurons of the arcuate nucleus that not only express NPY but also contain leptin receptors. In addition, hypocretin-containing neurons also express leptin receptor immunoreactivity. This suggests a potential mechanism of action for hypocretin in the central regulation of metabolic and endocrine processes. The excitatory actions of hypocretin could increase NPY release, resulting in enhanced feeding behavior and altered endocrine regulation, whereas leptin, released from adipose tissue as an indicator of fat stores, would have the opposite effect on the same neurons, leading to a decrease in NPY and NPY-mediated hypothalamic functions. On the other hand, the innervation of hypocretin cells by NPY boutons raises the possibility that NPY may exert an effect on hypothalamic functions, at least in part, via mediation or feedback action on these lateral hypothalamic cells. Our data indicate that a direct interaction between leptin, hypocretin, and NPY exists in the hypothalamus that may contribute to the central regulation of metabolic and endocrine processes in both rodents and primates.