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PACAP neurons in the hypothalamic ventromedial nucleus are targets of central leptin signaling.

Abstract
The adipose-derived hormone, leptin, was discovered over 10 years ago, but only now are we unmasking its downstream pathways which lead to reduced energy intake (feeding) and increased energy expenditure (thermogenesis). Recent transgenic models have challenged the long-standing supposition that the hypothalamic arcuate nucleus (Arc) is omnipotent in the central response to leptin, and research focus is beginning to shift to examine roles of extra-arcuate sites. Dhillon et al. (2006) demonstrated that targeted knock out of the signaling form of the leptin receptor (lepr-B) in steroidogenic factor 1 (SF-1) cells of the hypothalamic ventromedial nucleus (VMN) produces obesity of a similar magnitude to the pro-opiomelanocortin (POMC)-driven lepr-B deleted mouse, via a functionally distinct mechanism. These findings reveal that SF-1 cells of the VMN could be equally as important as POMC cells in mediating leptin's anti-obesity effects. However, the identification of molecular and cellular correlates of this relationship remains tantalizingly unknown. Here, we have shown that mRNA expression of the VMN-expressed neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is regulated according to energy status and that it exerts catabolic effects when administered centrally to mice. Furthermore, we have shown that SF-1 and PACAP mRNAs are colocalized in the VMN, and that leptin signaling via lepr-B is required for normal PACAP expression in these cells. Finally, blocking endogenous central PACAP signaling with the antagonist PACAP(6-38) markedly attenuates leptin-induced hypophagia and hyperthermia in vivo. Thus, it appears that PACAP is an important mediator of central leptin effects on energy balance.
AuthorsZoe Hawke, Tina R Ivanov, David A Bechtold, Harveen Dhillon, Brad B Lowell, Simon M Luckman
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 29 Issue 47 Pg. 14828-35 (Nov 25 2009) ISSN: 1529-2401 [Electronic] United States
PMID19940178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Leptin
  • Peptide Fragments
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Receptors, Leptin
  • Steroidogenic Factor 1
  • pituitary adenylate-cyclase-activating-peptide (6-38)
Topics
  • Animals
  • Appetite Regulation (physiology)
  • Body Weight (drug effects, physiology)
  • Energy Metabolism (drug effects, physiology)
  • Fever (drug therapy, metabolism, physiopathology)
  • Leptin (metabolism, pharmacology)
  • Male
  • Mice
  • Neurons (cytology, drug effects, metabolism)
  • Peptide Fragments (pharmacology)
  • Pituitary Adenylate Cyclase-Activating Polypeptide (genetics, metabolism, pharmacology)
  • Receptors, Leptin (drug effects, metabolism)
  • Signal Transduction (drug effects, physiology)
  • Steroidogenic Factor 1 (genetics, metabolism)
  • Ventromedial Hypothalamic Nucleus (cytology, metabolism)

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