Investigations on hypothalamic mechanisms for the increased appetite by orexin

Abstract

The neuropeptide orexin (or hypocretin) plays a key role in the regulation of wakefulness and appetite. Although there has been thorough research on the neurocircuitry associated with orexin-induced wakefulness, our understanding of the regarding neurons responsible for orexin-induced feeding remains incomplete. In this study, I found that orexin A directly activates the “appetite-suppressing” pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus to promote food intake. Employing various methods such as patch-clamp electrophysiology, immunohistochemistry, and in vivo feeding studies, we investigated the neuronal circuits underlying the orexigenic effects of orexin. I discovered evidence that orexin A causes the depolarization of the membrane potential of POMC neurons via the hypocretin receptor 2 (HcrtR2)-phospholipase C $\beta 4$ ($PLC \beta 4$) signaling pathway. Notably, my findings revealed that HcrtR2 and $PLC \beta 4$ expressed by POMC neurons is sufficient and necessary, respectively, for orexin A-induced feeding. Furthermore, the central opioid system is activated downstream of POMC neurons to increase food intake by orexin A. Together, this study uncovered the identity of the first-order neuron by which orexin promotes feeding.