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.