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It is widely accepted that leptin acts on first-order neurons in the arcuate nucleus (ARC) with information then relayed to other hypothalamic centers. However, the extent to which leptin mediates its central actions solely, or even primarily, via this route is unclear. We used a model of hypothalamo-pituitary disconnection (HPD) to determine whether leptin action on appetite-regulating systems requires the ARC. This surgical preparation eliminates the ARC. We measured effects of iv leptin to activate hypothalamic neurons (Fos labeling). In ARC-intact animals, leptin increased the percentage of Fos-positive melanocortin neurons and reduced percentages of Fos-positive neuropeptide Y neurons compared with saline-treated animals. HPD itself increased Fos labeling in the lateral hypothalamic area (LHA). Leptin influenced Fos labeling in the dorsomedial nucleus (DMH), ventromedial nucleus, and paraventricular nucleus (PVN) in HPD and normal animals, with effects on particular cell types varying. In the LHA and DMH, leptin decreased orexin cell activation in HPD and ARC-intact sheep. HPD abolished leptin-induced expression of Fos in melanin-concentrating hormone cells in the LHA and in CRH cells in the PVN. In contrast, HPD accentuated activation in oxytocin neurons. Our data from sheep with lesions encompassing the ARC do not suggest a primacy of action of leptin in this nucleus. We demonstrate that first order to second order signaling may not represent the predominant means by which leptin acts in the brain to generate integrated responses. We provide evidence that leptin exerts direct action on cells of the DMH, ventromedial nucleus, and PVN.

In the present study, we investigated the role of prolactin (PRL) in the suckling-induced increase in hypothalamic neuropeptide Y (NPY) gene expression in the dorsomedial nucleus of the hypothalamus (DMH) and the caudal portion of the arcuate nucleus of the hypothalamus (ARH-C). Lactating rats were deprived of their eight-pup litters on d 9 postpartum. After 48 h, the animals were randomly divided into two groups: nonsuckled controls and eight pups suckling for 24 h. In addition, some of the suckled animals received two injections of bromocriptine (0.5 mg/rat per injection) to inhibit suckling-induced PRL secretion. Some bromocriptine-treated rats also received ovine PRL (1 mg/rat per injection). In situ hybridization was performed to measure NPY mRNA levels. Suckling for 24 h induced a significant increase in NPY mRNA levels in the DMH and ARH-C. Bromocriptine treatment greatly attenuated the increase of NPY mRNA in the DMH but not in the ARH. Injections of ovine PRL in bromocriptine-treated rats greatly restored DMH NPY mRNA levels but had no additional effects on the ARH NPY expression. Double-label in situ hybridization for NPY and PRL receptor (PRL-R) in the lactating rat brains showed that NPY-positive neurons in the DMH also express PRL-R mRNA. On the contrary, few ARH NPY neurons expressed PRL-R. These data suggest that PRL could act directly on DMH NPY neurons to modulate NPY gene expression during lactation. Thus, the results from the present study demonstrate that NPY neurons in the DMH and ARH are differentially regulated by PRL during lactation.

We have previously shown that TNF-alpha, a major proinflammatory cytokine, suppressed hypothalamic GnRH pulse generator activity and that this inhibitory effect was enhanced by alpha-helical CRH, a CRH receptor antagonist. The present study was conducted to elucidate the involvement of glucocorticoid (GC) in modulating LH pulses under infectious stress condition. Adrenalectomy (ADX) markedly enhanced the suppressive effect of TNF-alpha (1 micro g), injected iv, on LH pulses in ovariectomized (OVX) rats. Pretreatment with a sc injection of corticosterone (10 mg) almost completely restored LH pulses after TNF-alpha injection in OVX/ADX animals. Injection of TNF-alpha increased the number of c-Fos-immunoreactive cells in the supraoptic nucleus (SON), the dorsomedial hypothalamic nucleus (DMH), and the parvocellular region of the paraventricular nucleus (PVN), which was more prominent in OVX/ADX than OVX animals except in the DMH. Pretreatment with corticosterone decreased the number of Fos-immunoreactive cells in the PVN and SON but not in the DMH. These results suggest that GC has a potent protective effect on LH pulsatility under conditions of infectious stress, the mechanism of which involves at least the suppression of the excitability of PVN and SON neurons. In addition, the DMH does not seem to mediate the central action of GC, though it may play an important role in inducing pathophysiological reactions to invasive stress.