Abstract
Hypothalamic AMP-activated protein kinase (AMPK) and orexins/hypocretins are both involved in the control of feeding behavior, but little is known about the interaction between these two signaling systems. Here, we demonstrated that orexin-A elicited significant activation of AMPK in the arcuate nucleus (ARC) of the hypothalamus by elevating cytosolic free Ca2+ involving extracellular calcium influx. Electrophysiological results revealed that orexin-A increased the L-type calcium current via the orexin receptor–phospholipase C–protein kinase C signaling pathway in ARC neurons that produce neuropeptide Y, an important downstream effector of orexin-A’s orexigenic effect. Furthermore, the L-type calcium channel inhibitor nifedipine attenuated orexin-A–induced AMPK activation in vitro and in vivo. We found that inhibition of AMPK by either compound C (6-[4-[2-(1-piperidinyl)ethoxy]phenyl]-3-(4-pyridinyl)-pyrazolo[1,5-a]pyrimidine) or the ATP-mimetic 9-β-D-arabinofuranoside prevented the appetite-stimulating effect of orexin-A. This action can be mimicked by nifedipine, the blocker of the L-type calcium channel. Our results indicated that orexin-A activates hypothalamic AMPK signaling through a Ca2+-dependent mechanism involving the voltage-gated L-type calcium channel, which may serve as a potential target for regulating feeding behavior.
Footnotes
- Received April 6, 2013.
- Accepted September 24, 2013.
This work was supported by grants from the National Natural Science Foundation of China (NSFC; Grant 81222048) (to F.W.); the National Basic Research Program of China (973 Program, Grant 2013CB531303); the Key Project of the NSFC (Grant 30930104); and the International Science & Technology Cooperation Program of China (Grant 2011DFA32670) (to J.-G.C.).
W.-N.W., P.-F.W., and J.Z. contributed equally to this work.
This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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