Barbara Woodside

Effects of systemic and central prolactin injections on food intake, weight gain, and estrous cyclicity in female rats.

It has been suggested that prolactin may contribute to the hyperphagia of lactation. Studies examining the effects of the systemic administration of prolactin on food intake, however, have produced varying results. In species other than the rat, central prolactin administration has been found to increase food intake, but it is not known if central prolactin administration increases food intake in rats. In the current study the effects of peripheral and central prolactin administration on food intake, weight gain, and estrous cyclicity in female rats were compared. Prolactin was administered twice daily at 0800 and at 1900 h either subcutaneously at 3 mg/kg or 1 mg/kg b.wt. or by intracerebroventricular (ICV) infusion (2 micrograms/0.5 microliter) for 10 days to female rats. Control animals received similar injections of vehicle. Food intake, body weight, and vaginal smears were taken daily. Results showed that peripheral administration of prolactin increased food intake and weight gain and disrupted vaginal cyclicity. In contrast, ICV administration increased food intake to the same extent as did systemic prolactin administration but had no effect on weight gain or cyclicity. These data suggest that prolactin acts both peripherally and centrally to regulate energy balance in the female rat.

Maternity: neural mechanisms, motivational processes, and physiological adaptations.

This review focuses on research on both the neural substrate of maternal responsiveness and on the physiological, behavioral, and motivational adaptations to the maternal state. The females response to her young is presented as a model motivational system and the mechanisms and neural circuitry through which the medial preoptic area regulates this responsivity is described. This analysis is then used in support of an argument for a greater recognition of the role of hypothalamic nuclei in the stimulation of appetitive behavior. In the subsequent section of the manuscript the adaptations of other motivational systems to the maternal state together with the research investigating the mechanisms that produce these changes are described. Finally, we examine how these multiple adaptations may be coordinated and integrated.

Prolactin and the hyperphagia of lactation.

The nutritional needs of developing young place a large energetic demand on lactating females. In this paper some of the mechanisms through which lactating rats meet these demands are described. Emphasis is placed on the mechanisms that drive increased food intake in suckled rats that are independent of milk delivery and negative energy balance. Evidence is presented to suggest that prolactin (PRL), released from the pituitary in response to suckling stimulation, acts centrally to stimulate food intake during lactation. Brain areas in which PRL may act to stimulate food intake as well as its interactions with other hormones and neuropeptides involved in energy balance are discussed.

Changes in leptin levels during lactation: implications for lactational hyperphagia and anovulation.

In these studies we investigated the time course of changes in circulating leptin levels in lactating rats and the dependence of these changes on the energetic cost of lactation and evaluated the contribution of changes in leptin levels to lactational hyperphagia and infertility. In the first experiment, plasma leptin levels were measured on Days 5, 10, 15, 20, and 25 postpartum in freefeeding lactating rats and age-matched virgin females. Retroperitoneal and parametrial fat pads weights were obtained from the same females. In the second experiment the same measures, together with plasma insulin and prolactin levels, were taken on Days 15 and 20 postpartum from galactophore-cut and sham-operated females. In Experiments 3 and 4, the effects of exogenous leptin administration, either subcutaneously (sc) or intracerebroventricularly (icv), on lactational anovulation, maternal food intake, and dam and litter weights were examined. Circulating leptin levels decreased in lactating rats. Leptin levels were highly positively correlated with fat pad weight. Eliminating the energetic costs of lactation by preventing milk delivery induced dramatic increases in plasma leptin and insulin levels and also increased adiposity. Exogenous leptin administration did not affect length of lactational anovulation but reduced food intake, maternal body weight, and litter weight gain when given centrally and maternal body weight when given systemically. Together, these data show that the energetic costs of lactation are associated with a fall in circulating leptin levels but that these do not make a major contribution to the suppression of reproduction in lactating rats; however, they may be permissive to the hyperphagia of lactation.

The effect of central administration of prolactin on food intake in virgin female rats is dose-dependent, occurs in the absence of ovarian hormones and the latency to onset varies with feeding regimen.

Lactation in mammals is characterized by a marked hyperphagia and significantly elevated levels of prolactin (PRL). Several recent experiments in our laboratory have provided evidence for a causal relationship between PRL and hyperphagia. The present series of studies revealed that PRL injected intracerebroventricularly (i.c.v.) twice daily for ten days to free feeding virgin female rats produced a dose-dependent increase in food intake without disrupting vaginal cyclicity, that the hyperphagic effect of centrally administered PRL was not dependent on the presence of ovarian hormones, that it did not selectively potentiate feeding during the light or dark phase of the daily light cycle and that the latency of the feeding response to i.c.v. PRL administration was shorter in food restricted animals. Taken together, these results support the idea that PRL acts centrally to potentiate food intake.

Neuroanatomical specificity of prolactin-induced hyperphagia in virgin female rats

Intracerebroventricular (i.c.v.) administration of PRL increases food intake in virgin female rats but the brain site(s) at which PRL acts to promote feeding behavior is not known. The present studies investigated the role of the paraventricular nucleus (PVN), ventromedial nucleus (VMH), and medial preoptic nucleus (MPOA) in the hyperphagic actions of PRL. Ad-libitum-fed virgin female rats received twice daily site-specific injections of PRL (800 ng) over a period of 10 days. Only subjects demonstrating regular vaginal cyclicity were included in the study. Food intake, body weight, and vaginal cyclicity were measured daily. Results showed that PRL significantly increased food intake when injected into the PVN. A nonsignificant trend towards a hyperphagic response in the last 5 days of testing was observed in rats receiving intra-VMH injections of PRL, and the MPOA was not responsive to the feeding-stimulating properties of PRL. None of the manipulations affected body weight or vaginal cyclicity as demonstrated by vaginal smears. In sum, the present results reveal that one brain site at which PRL acts to increase food intake is the PVN, but these studies do not rule out the possibility that the effects of PRL on food intake may also involve other brain areas.

Changes in hypothalamically mediated acute-phase inflammatory responses to lipopolysaccharide in diet-induced obese rats.

Recent evidence suggests that inflammation may be a common underlying cause of many obesity-associated conditions. To test whether obesity changes the response to inflammation, we investigated its effects on the acute phase of the inflammatory response to an endogenous pathogen, lipopolysaccharide (LPS). Diet-induced obese male Wistar rats exhibited an increased and prolonged fever response to LPS (100 microg/kg) relative to lean rats. LPS-treated obese rats also showed a greater increase in circulating TNF-alpha, IL-6, and IL-1 receptor antagonist within the first 8 h after LPS injection. LPS induced an increase in circulating leptin only in obese rats with no effect in lean rats. Analysis of expression of pyrogenic signaling in the hypothalamus demonstrated that obese rats show a greater increase in IL-1beta peaking at 2 h after LPS injection and suppressor of cytokine signaling 3 and IL-6 peaking at the 8-h time point. LPS-treated obese rats showed a significantly higher expression of IL-1 receptor antagonist in white adipose tissue (WAT) than lean rats, and WAT from obese rats incubated in LPS-supplemented medium (100 ng/ml) secreted a significantly higher level of IL-6. Overall, these results suggest that diet-induced obesity induces changes in the inflammatory response rendering the obese rats more responsive to the effects of LPS. These data also support the hypothesis that qualitative changes in WAT associated with obesity may contribute to these effects.

Signal-centered action patterns of dogs in appetitive classical conditioning

Abstract The movements of five unrestrained dogs were monitored during discriminative Pavlovian conditioning. An auditory-visual stimulus from one source (CS+) was followed by meat morsels (US); the same stimulus from another source (CS−) was not. Sources were equidistant from the site of US delivery. Before each trial, animals were required to position themselves at a starting location equidistant from both sources and removed from the US site. The stable behavior pattern in most subjects included approach to and contact or near contact with CS+, followed by approach to the US site. Dogs showed individually distinctive action patterns to CS+, in some cases suggestive of soliciting, in another of sight-pointing. Similar actions were not evoked by CS−. In postacquisition tests, patterns were generally unaffected by increased deprivation or by relocating the starting position next to the US site. The auditory component of CS+ was more effective than the visual. With a response-contingent procedure animals were successfully trained to approach the US site directly, although many trials, and in one case a special procedure, were required. It was proposed that the experimental signaling arrangement mimics a natural signaling sequence and induces appetitive behavior to the CS that corresponds to the behavior induced by certain natural signals of the US.

Brain reward circuitry and the regulation of energy balance

Reward signals contribute to the regulation of energy balance by influencing switching between feeding and competing behaviors. Properties of natural rewards are mimicked by electrical stimulation of certain brain regions. The rewarding effect produced by stimulating the perifornical region of the hypothalamus is modulated by body weight and is attenuated both by leptin and insulin. Research is reviewed concerning the dependence of the rewarding effect of perifornical stimulation on long-term energy stores and the effects of two neuropeptides implicated in the regulation of energy balance, neuropeptide Y and corticotropin-releasing hormone. It is proposed that the potentiating effect of weight loss on perifornical self-stimulation is not tied to an increased propensity to eat or to an enhancement of food reward per se, but resembles the influence of long-term energy stores on non-ingestive behaviors that defend body weight, such as hoarding.

Chronic Leptin Administration in Developing Rats Reduces Stress Responsiveness Partly through Changes in Maternal Behavior

In adult rodents, leptin has been shown to significantly alter the activity of several neuroendocrine functions, including the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Leptin is generally believed to be inhibitory to HPA activity in adults. Developing rat pups have high circulating levels of leptin, which begs the question of leptins physiological role in controlling basal and stress-induced adrenocortical activity in neonatal rats. In this study, we treated rat pups daily from days 2-9 (or 6-10) of life with either vehicle or leptin (1 or 3 mg/kg body wt, ip) and determined the effects on body weight gain, fat pad deposits, and HPA activity in 10-day-old pups. We measured hypothalamic CRF mRNA levels in vehicle- and leptin-treated pups by in situ hybridization and determined plasma ACTH, corticosterone, and leptin concentrations under basal conditions or following exposure to a 3-min ether stress. Because leptin activates sympathetic activity and energy expenditure in adults and possibly also in rat pups, and because litter temperature is an important determinant of maternal behavior, we also investigated whether chronic leptin administration would modify aspects of maternal care that are important for the maintenance of HPA function. Chronic leptin treatment increased circulating levels of leptin and had significant dose-related metabolic effects, including reduced body weight gain and fat pad weight in 10-day-old pups. Basal expression of CRF mRNA in the PVN or secretion of ACTH and corticosterone was not modified by leptin treatment. In contrast, chronically elevated leptin concentrations during the neonatal period significantly lowered CRF expression in the PVN 60 min after stress and reduced the duration of the ACTH response to stress in pups, suggesting that glucocorticoid feedback on the HPA axis might be altered by this treatment. In addition, mothers caring for pups injected with leptin displayed longer bouts of anogenital licking of pups than mothers of vehicle-treated rats. Given that this particular type of pup stimulation has been shown to influence stress responsiveness, it is possible that the maternal response modulates the effects of exogenous leptin treatment. In conclusion, our results demonstrate that the leptin signal is functional during the early developmental period and that leptin can modulate the hormonal response to stress in young rats either by a direct effect on the HPA axis or indirectly through changing some aspects of maternal behavior.