Feeding in mammals is a periodic behavior; however, knowledge of how the brain signals an intermittent eating pattern is scanty. Recent indirect evidence indicates that one of the signals encoded in the structure of neuropeptide Y (NPY) is to stimulate robust feeding. Therefore, two series of experiments were undertaken to characterize NPY secretion within the paraventricular nucleus (PVN) in association with eating behavior in the rat. Dynamic changes in NPY concentration in several hypothalamic sites and release in the PVN were assessed before and during the course of food consumption in rats trained to eat daily only for 4 h. Only in the PVN were NPY concentrations elevated before the introduction of food and, thereafter, levels decreased significantly during the course ofeating. A similar temporal pattern in NPY release into the PVN interstitium was evident in samples collected by push-pull cannula perfusion in unrestrained rats. In addition, in food-deprived rats displaying a robust drive for feeding, NPY release in the PVN was also markedly enhanced in the shape of high-amplitude secretory episodes as compared to a lower release rate in rats receiving food ad libitum. The higher rate of NPY release in fasted rats returned to the control range after 24 h of ad libitum food supply. These rmdings of intense and dynamic NPY neurosecretory activity within a discrete hypothalamic site in association with an increased drive for food consumption demonstrate that NPY release in the PVN is an important orexigenic signal for periodic eating behavior. These results have important global implications for elucidating the underlying causes of the pathophysiology of eating disorders-anorexia nervosa, bulimia, and obesity-as well as constituting a specific contextual model for the formulation and testing of suitable NPY receptor agonists and antagonists for therapeutic intervention.Neural circuits that integrate metabolic, neural, and hormonal signals leading to intermittent motivation to eat reside in the hypothalamus. There is now a consensus that stimulation of hunger or appetite for food is encoded in a few specific signals in the hypothalamus. Among peptides and amines that stimulate feeding, neuropeptide Y (NPY) is found to be the most potent enhancer of consummatory behavior in a large number of species (1-4). NPY is produced in the arcuate nucleus (ARC) ofthe hypothalamus and other regions of the brain, including discrete cell groups in the brainstem. The fiber systems from the ARC and brainstem project into various hypothalamic sites previously implicated in regulation of feeding behavior (5-8). In fact, not only administration into the cerebroventricular system (3, 9, 10) but microinjection of NPY into various hypothalamic sites (11-13) rapidly elicited robust feeding responses in rats. Continuous NPY infusion into the third cerebroventricle evoked continuous episodic feeding during the infusion and postinfusion intervals (14). Multiple daily injections of NPY into the paraventricular nucleus (PVN) of the...

Various aspects of the complex spatio-temporal patterning of hypothalamic signaling that leads to the development of synchronized nocturnal feeding in the rat are critically examined. Undoubtedly, as depicted in Fig. 7, a distinct ARN in the hypothalamus is involved in the control of nocturnal appetite. At least four basic elements operate within this ARN. These are: 1) A discrete appetite-driving or orexigenic network of NPY, NE, GABA, GAL, EOP, and orexin transduces and releases appetite-stimulating signals. 2) Similarly, anorexigenic signal-producing pathways (e.g., CRH, GLP-1, alpha MSH, and CART) orchestrate neural events for dissipation of appetite and to terminate feeding, possibly by interrupting NPY efflux and action at a postsynaptic level within the hypothalamus. It is possible that some of these may represent the physiologically relevant "off" switches under the influence of GABA alone, or AgrP alone, or in combination with NPY released from the NPY-, GABA-, and AgrP-coproducing neurons. 3) Recent evidence shows that neural elements in the VMN-DMN complex tonically restrain the orexigenic signals during the intermeal interval; the restraint is greatly aided by leptin's action via diminution of orexigenic (NPY) and augmentation of anorexigenic (GLP-1, alpha MSH, and CART) signals. Since interruption of neurotransmission in the VMN resulted in hyperphagia and development of leptin resistance, it seems likely that the VMN is an effector site for the restraint exercised by leptin. The daily rhythms in leptin synthesis and release are temporally dissociable because the onset of daily rise in leptin gene expression in adipocytes precedes that in leptin secretion. Nevertheless, these rhythms are in phase with daily ingestive behavior because the peak in circulating leptin levels occurs during the middle of the feeding period. These observations, coupled with the fact that circulating levels of leptin are directly related to adiposity, pose a new challenge for elucidating the precise role of leptin in daily patterning of feeding in the rat. 4) A neural timing mechanism also operates upstream from the ARN in the daily management of energy homeostasis. Although the precise anatomical boundaries are not clearly defined, this device is likely to be composed of a group of neurons that integrate incoming internal and external information for the timely onset of the drive to eat. Evidently, this network operates independently in primates, but it is entrained to the circadian time keeper in the SCN of rodents. Apart from its role in the onset of drive to eat, the circadian patterns of gene expression of NPY, GAL, and POMC denote independent control of the timing device on the synthesis and availability for release of orexigenic signals. The VMN-DMN-PVN complex is apparently an integrated constituent of the timing mechanism in this context, because lesions in each of these sites result in loss of regulated feeding. The accumulated evidence points to the PVN and surrounding neural sites within this framework as the pri...

We tested the hypothesis that leptin acts centrally and peripherally by different mechanisms to control peripheral hormones that normally regulate weight homeostasis. The paradigm of selectively increasing leptin transgene expression with a single intracerebroventricular injection of adeno-associated viral vectors encoding leptin (rAAV-lep) or green fluorescent protein (control) in the hypothalamus of mutant leptin-deficient ob/ob and wild-type (wt) mice was employed in these experiments. rAAV-lep injection increased hypothalamic leptin expression in the complete absence of peripheral leptin in ob/ob mice; suppressed body weight and adiposity; voluntarily decreased dark-phase food intake; suppressed plasma levels of adiponectin, TNFalpha, free fatty acids and insulin, concomitant with normoglycemia; and elevated ghrelin levels for extended period. Body weight and plasma levels of leptin and metabolic variables were suppressed to a lesser extent in rAAV-lep wt mice without decreasing food intake. The sustained high leptin transgene expression decreased only the dark-phase phagia in both genotypes, but wt mice escaped from leptin restraint during the lights-on phase, resulting in normal overall food intake. Leptin administration rapidly decreased plasma gastric ghrelin and adipocyte adiponectin but not TNFalpha levels, thereby demonstrating a peripheral restraining action of leptin on the secretion of hormones of varied origins. Whereas ghrelin administration readily stimulated feeding in controls, it was completely ineffective in rAAV-lep-treated wt mice. Thus, leptin expressed locally in the hypothalamus counteracted the central orexigenic effects of peripheral ghrelin. Cumulatively, these results identify newer central and peripheral modulatory influences of leptin on hormonal signals of disparate origin implicated in weight homeostasis and metabolic disorders.