PT  - JOURNAL ARTICLE
AU  - Zoe Hawke
AU  - Tina R. Ivanov
AU  - David A. Bechtold
AU  - Harveen Dhillon
AU  - Brad B. Lowell
AU  - Simon M. Luckman
TI  - PACAP Neurons in the Hypothalamic Ventromedial Nucleus Are Targets of Central Leptin Signaling
AID  - 10.1523/JNEUROSCI.1526-09.2009
DP  - 2009 Nov 25
TA  - The Journal of Neuroscience
PG  - 14828--14835
VI  - 29
IP  - 47
4099  - http://www.jneurosci.org/content/29/47/14828.short
4100  - http://www.jneurosci.org/content/29/47/14828.full
SO  - J. Neurosci.2009 Nov 25; 29
AB  - 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 PACAP6-38 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.