Energetic demands of lactation produce an increase in the expression of growth hormone secretagogue receptor in the hypothalamus and ventral tegmental area of the rat despite a reduction in circulating ghrelin.

Lactating rats show changes in the secretion of hormones and brain signals that promote hyperphagia and facilitate the production of milk. Little is known, however, about the role of ghrelin in the mechanisms sustaining lactational hyperphagia. Here, we used Wistar female rats that underwent surgery to sever the galactophores to prevent milk delivery (GC rats) and decrease the energetic drain of milk delivery. We compared plasma acyl-ghrelin concentrations and growth hormone secretagogue receptor (GHSR) mRNA expression in different brain regions of GC rats with those of sham operated lactating and nonlactating rats. Additional lactating and nonlactating rats were implanted with cannulae aimed at the lateral ventricles and were used to compare feeding responses to central ghrelin or GHSR antagonist infusions to those of nonlactating rats receiving similar infusions on day 14-16 postpartum (pp). Results show lower plasma acyl-ghrelin concentrations on day 15 pp sham operated lactating rats compared to GC or nonlactating rats. These changes occur in association with increased GHSR mRNA expression in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA) of sham operated lactating rats. Despite lactational hyperphagia, infusions of ghrelin (0.25 or 1 µg) resulted in similar increases in food intake in lactating and nonlactating rats. In addition, infusions of the GHSR antagonist JMV3002 (4 µg in 1 µl of vehicle) produced greater suppression of food intake in lactating rats than in nonlactating rats. These data suggest that, despite lower plasma ghrelin, the energetic drain of lactation increases sensitivity to the orexigenic effects of ghrelin in brain regions important for food intake and energy balance, and these events are associated with lactational hyperphagia.

Leptin modulates the late fever response to LPS in diet-induced obese animals.

Leptin is an important modulator of both inflammation and energy homeostasis, making it a key interface between the inflammatory response to pathogenic stimuli and the energy status of the host. In previous studies we demonstrated that sickness responses to systemic immune challenge, including fever, are significantly exacerbated in diet induced obese animals. To investigate whether this exacerbation is functionally linked to the obesity associated increase in circulating levels of leptin, a species-specific leptin antiserum (LAS) was used to neutralize endogenous leptin in diet-induced obese adult male Wistar rats treated with a single intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) (100µg/kg). LAS significantly reduced the magnitude of the later phases of the fever response, and attenuated the circulating levels of IL-6, IL-1ra and bioactivity of leptin in the obese animals. In addition, the antiserum significantly attenuated the hypothalamic expression of IL-1ß, IκBα, COX2, SOCS3 and IL-6 in both lean and obese rats 10h after the LPS injection and NF-IL6 in the hypothalamus of obese rats only. The relatively late rise in brain IL-6 suggested a role in mediating the extended fever response in obese animals and we tested this by neutralizing brain IL-6 using an IL6-AS injected intracerebroventricularly (4µl, icv). The IL6-AS significantly but transiently (between 9h and 12h post LPS) reduced the late fever response of obese rats. These results demonstrate that leptin plays an important part in modulating the late portion of the fever response to LPS, likely through the induction of hypothalamic IL-6 in obese animals.

The effects of dietary saturated fat on basal hypothalamic neuroinflammation in rats.

Recent evidence has demonstrated that consumption of high fat diets can trigger brain inflammation and subsequent injury in the absence of any peripheral inflammatory signaling. Here we sought to investigate whether a link exists between the concentration of highly saturated fats in the diet and the development of inflammation in the brain of rats and, whether the source of the saturated fat was an important factor in this process. Adult male rats had access to diets with a moderate level of total fat (32% of calories as fat) varying in level of saturated fat [low (20%) vs high (>60%)] and its source (butter or coconut oil). After 8 weeks of diet exposure peripheral and central tissues were collected for analysis of inflammatory signals. Neither blood nor white adipose tissue exhibited any changes in inflammatory mediators regardless of the saturated fat content or the source. In the brain however, we observed significant hypothalamic upregulation of the expression of markers of glial activation as well as of interleukin (IL)-1,6 and nuclear factor (NF)-IL-6, which were highest in the group fed the butter-based diets. The increase in these inflammatory mediators had no effect on basal body temperature or the temperature response to systemic lipopolysaccharide (LPS). The present results indicate that hypothalamic inflammation associated with consumption of diets high in fat is directly linked to the saturated fat content as well as the source of that fat. These effects are likely linked to other pathophysiological changes in the regulation of metabolism.

Many mouths to feed: the control of food intake during lactation.

Providing nutrients to their developing young is perhaps the most energetically demanding task facing female mammals. In this paper we focus primarily on studies carried out in rats to describe the changes in the maternal brain that enable the dam to meet the energetic demands of her offspring. In rats, providing milk for their litter is associated with a dramatic increase in caloric intake, a reduction in energy expenditure and changes in the pattern of energy utilization as well as storage. These behavioral and physiological adaptations result, in part, from alterations in the central pathways controlling energy balance. Differences in circulating levels of metabolic hormones such as leptin, ghrelin and insulin as well as in responsiveness to these signals between lactating and nonlactating animals, contribute to the modifications in energy balance pathways seen postpartum. Suckling stimulation from the pups both directly, and through the hormonal state that it induces in the mother, plays a key role in facilitating these adaptations.

Long-term physiological and behavioral effects of exposure to a highly palatable diet during the perinatal and post-weaning periods.

Environmental conditions promote weight gain in children and adults, with early nutritional states and the availability of energy condensed/high-fat palatable diets appearing to facilitate the development of obesity. Little is known about the extent to which prenatal and postnatal dietary manipulations alter the response of the adult offspring to high-fat, highly palatable diets. Here we exposed rat dams to highly palatable diet (supplemental diet, SD), rich in fat and sugars, during pregnancy and lactation, and assessed the potential interactions with the effects of a similar diet offered post-weaning on a range of physiological and behavioral parameters in the adult male offspring. Post-weaning exposure to SD increased body weight, body fat, and plasma leptin levels, as well as the plasma glucose response to glucose challenge, compared to chow-fed rats. Combining perinatal SD with post-weaning exposure (SD/SD group) elevated fasting plasma glucose levels, and induced leptin resistance in the adult rats. The same treatment also resulted in sensitized locomotor response to an acute injection of amphetamine. The glucocorticoid response to stress was not affected by the dietary treatments. We conclude that exposure of mother and young to a highly palatable diet with high-fat and high sugar content during the critical perinatal period, increases the risk of developing an obesity-like condition in rats exposed to the same palatable diet post-weaning, and this effect may be accompanied by adaptations in the reward-related mesostriatal dopaminergic system.

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.

Interaction of CRH and energy balance in the modulation of brain stimulation reward.

The rewarding effect produced by electrical stimulation of some lateral hypothalamic sites is modulated by chronic food restriction and weight loss. The sensitivity of the rewarding effect to restriction predicts the modulation of brain stimulation reward (BSR) by the adiposity hormone, leptin. The present study examined the effect of corticotropin-releasing hormone (CRH) on the rewarding effect of stimulating restriction-sensitive and restriction-insensitive sites. Chronic food restriction reduced frequency thresholds for BSR in half of the subjects but had no effect in the others. CRH increased thresholds only in subjects in which the rewarding effect was insensitive to restriction. In contrast, frequency thresholds remained stable in nearly all rats with restriction-sensitive stimulation sites. These findings provide further evidence that sensitivity to food restriction is an important factor in determining the influence of hormones and neuropeptides on brain reward circuitry.