Search

Hypoxia-inducible factor-1α (HIF-1α) is an important regulator of glucose metabolism and inflammatory cytokine production in innate immune responses. Viruses modulate HIF-1α to support viral replication and the survival of infected cells, but it is unclear if this transcription factor also plays an important role in regulating antiviral immune responses. In this study, we found that short and long dsRNA differentially engage TLR3, inducing distinct levels of proinflammatory cytokine production (TNF-α and IL-6) in bone marrow–derived macrophages from C57BL/6 mice. These responses are associated with differential accumulation of HIF-1α, which augments NF-κB activation. Unlike TLR4 responses, increased HIF-1α following TLR3 engagement is not associated with significant alterations in glycolytic activity and was more pronounced in low glucose conditions. We also show that the mechanisms supporting HIF-1α stabilization may differ following stimulation with short versus long dsRNA and that pyruvate kinase M2 and mitochondrial reactive oxygen species play a central role in these processes. Collectively, this work suggests that HIF-1α may fine-tune proinflammatory cytokine production during early antiviral immune responses, particularly when there is limited glucose availability or under other conditions of stress. Our findings also suggest we may be able to regulate the magnitude of proinflammatory cytokine production during antiviral responses by targeting proteins or molecules that contribute to HIF-1α stabilization.

Emerging adults, including post-secondary education students, are disproportionately affected by the social and economic impacts of the COVID-19 pandemic. The speed with which society moved in attempt to minimize the spread of the virus left many students with uncertainty and concern about their health, mental health, and academic futures. Considering that post-secondary students are a population at risk, it is important to determine how students respond in the face of the pandemic, and what coping mechanisms or supports will result in improved mental health outcomes. This knowledge will be helpful for post-secondary institutions to understand how COVID-19 has influenced the health and well-being of their students, and may facilitate the implementation of strategies to support their students. This narrative review explores evidence on how COVID-19 has impacted students with the overall goal to provide a set of recommendations to post-secondary institutions to help meet the evolving needs of this population.

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.

Ghrelin and the growth hormone secretagogue receptor 1a (GHS-R1a) are important targets for disorders related to energy balance and metabolic regulation. Pharmacological control of ghrelin signaling is a promising avenue to address health issues involving appetite, weight gain, obesity, and related metabolic disorders, and may be an option for patients suffering from wasting conditions like cachexia. In this review, we summarize recent developments in the biochemistry of ghrelin and GHS-R1a signaling. These include unravelling the enzymatic transformations that generate active ghrelin and the discovery of multiple proteins that interact with ghrelin and GHS-R1a to regulate signaling. Furthermore, we propose that harnessing these processes will lead to highly selective treatments to address obesity, diabetes, and other metabolism-linked disorders.

Chronic exposure to high circulating glucocorticoid or ghrelin concentrations increases food intake, weight gain and adiposity, suggesting that ghrelin could contribute to the metabolic effects of chronic glucocorticoids. In male mice, however, blocking ghrelin receptor (GHSR) signaling increased the weight gain and adiposity induced by chronic corticosterone (CORT), rather than attenuating them. In the current study, we investigated the role of GHSR signaling in the metabolic effects of chronic exposure to high circulating CORT in female mice. To do this, female WT and GHSR KO mice were treated with either CORT in a 1% ethanol (EtOH) solution or 1% EtOH alone in their drinking water for 32 days (n = 5–8/group). Body weight, food, and water intake as well as vaginal cyclicity were assessed daily. As expected, CORT treatment-induced significant increases in body weight, food intake, adiposity and also impaired glucose tolerance. In contrast to results observed in male mice, WT and GHSR KO female mice did not differ on any of these parameters. Neither plasma levels of ghrelin, LEAP-2, the endogenous GHSR antagonist produced by the liver, nor their ratio were altered by chronic glucocorticoid exposure. In addition, CORT treatment disrupted vaginal cyclicity, produced a reduction in sucrose consumption and increased locomotor activity regardless of genotype. Chronic CORT also decreased exploration in WT but not GHSR KO mice. Collectively, these data suggest that most metabolic, endocrine, reproductive and behavioral effects of chronic CORT exposure are independent of GHSR signaling in female mice.

Most psychiatric disorders are characterized by deficits in the ability to interact socially with others. Ghrelin, a hormone normally associated with the regulation of glucose utilization and appetite, is also implicated in the modulation of motivated behaviors including those associated with food and sex rewards. Here we hypothesized that deficits in ghrelin receptor (growth hormone secretagogue receptor; GHSR) signaling are also associated with deficits in social motivation in male mice. To test this hypothesis, we compared social motivation in male mice lacking GHSR or mice treated with the GHSR antagonist JMV2959 with that of WT or vehicle-treated mice. GHSR signaling in dopamine cells of the ventral tegmental area (VTA) has been implicated in the control of sexual behavior, thus we further hypothesized that GHSR signaling in the VTA is important for social motivation. Thus, we conducted studies where we delivered JMV2959 to block GHSR in the VTA of mice, and studies where we rescued the expression of GHSR in the VTA of GHSR knockout (KO) mice. Mice lacking GHSR or injected with JMV2959 peripherally for 3 consecutive days displayed lower social motivation as reflected by a longer latency to approach a novel conspecific and shorter interaction time compared to WT or vehicle-treated controls. Furthermore, intra-VTA infusion of JMV2959 resulted in longer latencies to approach a novel conspecific, whereas GHSR KO mice with partial rescue of the GHSR showed decreased latencies to begin a novel social interaction. Together, these data suggest that GHSR in the VTA facilitate social approach in male mice, and GHSR-signaling deficits within the VTA result in reduced motivation to interact socially.

The ancient Egyptians used willow bark as a remedy for aches and pains, even though they were unaware that salicylic acid was responsible for its anti-pyrogenic and anti-inflammatory actions.[1][1] Based on anecdotal reports and social media chatter, cannabis might yet displace salicylic acid as the

Bisphenol-A (BPA) is a well-known endocrine disrupting compound (EDC), capable of affecting the normal function and development of the reproductive system, brain, adipose tissue, and more. In spite of these diverse and well characterized effects, there is often comparatively little known about the molecular mechanisms which bring them about. BPA has traditionally been regarded as a primarily estrogenic EDC, and this perspective is often what guides research into the effects of BPA. However, emerging data from in-vitro and in-silico models show that BPA binds with a significant number of hormone receptors, including a number of nuclear and membrane-bound estrogen receptors, androgen receptors, as well as the thyroid hormone receptor, glucocorticoid receptor, and PPARγ. With this increased diversity of receptor targets, it may be possible to explain some of the more puzzling aspects of BPA pharmacology, including its non-monotonic dose-response curve, as well as experimental results which disagree with estrogenic positive controls. This paper reviews the receptors for which BPA has a known interaction, and discusses the implications of taking these receptors into account when studying the disruptive effects of BPA on growth and development.

Chronically elevated levels of glucocorticoids increase food intake, weight gain, and adiposity. Similarly, ghrelin, a gut-secreted hormone, is also associated with weight gain, adiposity, and increased feeding. Here we sought to determine if corticosterone-induced metabolic and behavioral changes require functional ghrelin receptors (GHSR). To do this, we treated male C57BL mice with chronic corticosterone (CORT) mixed in their drinking water for 28 days. Half of these mice received the GHSR antagonist JMV2959 via osmotic minipumps while treated with CORT. In a second experiment, we gave the same CORT protocol to mice with a targeted mutation to the GHSR or their wild-type littermates. As expected, CORT treatment increased food intake, weight gain, and adiposity, but contrary to expectations, mice treated with a GHSR receptor antagonist or GHSR knockout (KO) mice did not show attenuated food intake, weight gain, or adiposity in response to CORT. Similarly, the effects of CORT on the liver were the same or more pronounced in GHSR antagonist-treated and GHSR KO mice. Treatment with JMV2959 did attenuate the effects of chronic CORT on glycemic regulation as determined by the glucose tolerance test. Finally, disruption of GHSR signaling resulted in behavioral responses associated with social withdrawal, potentially due to neuroprotective effects of GHSR activation. In all, we propose that blocking GHSR signaling helps to moderate glucose concentrations when CORT levels are high, but blocking GHSR signaling does not prevent increased food intake, weight gain, or increased adiposity produced by chronic CORT.

Increasing evidence suggests that mitochondria play a critical role in driving innate immune responses against bacteria and viruses. However, it is unclear if differential reprogramming of mitochondrial function contributes to the fine tuning of pathogen specific immune responses. Here, we found that TLR3 and TLR4 engagement on murine bone marrow derived macrophages was associated with differential remodeling of electron transport chain complex expression. This remodeling was associated with differential accumulation of mitochondrial and cytosolic ROS, which were required to support ligand specific inflammatory and antiviral cytokine production. We also found that the magnitude of TLR3, but not TLR4, responses were modulated by glucose availability. Under conditions of low glucose conditions, TLR3 engagement was associated with increased ETC complex III expression, increased mitochondrial and cytosolic ROS and increased inflammatory and antiviral cytokine production. This amplification was selectively reversed by targeting superoxide production from the outer Q-binding site of the ETC complex III. These results suggest that ligand specific modulation of the ETC may act as a rheostat that fine-tunes innate immune responses via mitochondrial ROS production. Modulation of these processes may represent a novel mechanism to modulate the nature as well as the magnitude of antiviral versus inflammatory immune responses.

Made available in DSpace on 2018-11-26T17:45:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-02-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Natural Sciences and Engineering Research Council of Canada (NSERC) Developmental programing is influenced by perinatal nutrition and it has long-lasting impacts on adult metabolism in the offspring. In particular, maternal high fat diet has been associated with increased risk of obesity and metabolic disorders during adulthood in the descendants. These effects may be due to the effects of the high fat diet on the development of the systems that regulate food intake and energy balance in the offspring hypothalamus. The arcuate nucleus (ARC) may be a particularly sensitive region to it as this nucleus contains the POMC and AgRP/NPY neurons that integrate the melanocortin system. Thus, the aim of this study was to investigate the effects of maternal high fat diet during pregnancy on the transcription factors that regulate hypothalamic development in the offspring as a potential mechanism that may result in altered neuronal expression of POMC, NPY and/or AgRP. To this end, pregnant females exposed to high fat diet (60% fat diet since day 0 of pregnancy) or standard rat chow were sacrificed on days 12, 14, 16 and 18 of gestation to obtain brains from their developing fetuses and examine the mRNA expression of transcription factors associated with the development of cells in the ARC. Results show that, while no changes in transcription factor expression between groups were observed, POMC and NPY mRNA expression were higher on embryonic day 18 in the high fat group. These results suggest that POMC and NPY expression are altered by in utero exposure to a high fat diet, but these changes in gene expression are not associated with changes in the expression of transcription factors known to determine the fate of ARC cells. (C) 2017 ISDN. Published by Elsevier Ltd. All rights reserved. Carleton Univ, Dept Neurosci, 1125 Colonel Dr,Room 329, Ottawa, ON K1S 5B6, Canada Univ Sao Paulo, Dept Pharmacol, Inst Biomed Sci, Sao Paulo, SP, Brazil Sao Paulo State Univ, Dept Physiol, Botucatu, SP, Brazil Univ Sao Paulo, Sch Vet Med, Dept Pathol, Sao Paulo, SP, Brazil Sao Paulo State Univ, Dept Physiol, Botucatu, SP, Brazil FAPESP: 2012/07378-6 FAPESP: 2014/06980-0 Natural Sciences and Engineering Research Council of Canada (NSERC): 341538

Bisphenol-A (BPA) is a component of polycarbonate and other plastics to which humans are regularly exposed at low levels. BPA is characterized as an endocrine disruptor because of observations of its estrogenic activity in various experimental models. We have previously shown evidence of disrupted hypothalamic feeding circuitry and leptin sensitivity in adult BPA-exposed animals subjected to a high-fat diet, but because these animals were already exhibiting a diet-induced obese phenotype, we could not rule out the possibility that these observations were simply consequences of the obesity, not a preexisting phenotype produced by BPA exposure. Here, we studied leptin sensitivity and hypothalamic structure in young BPA-exposed animals before the onset of a body weight or metabolic phenotype. Pregnant and lactating CD-1 mice were exposed to either BPA or diethylstilbestrol (DES) at low, environmentally relevant doses via their diet. Studies of leptin function and neurobiology were conducted on offspring at several time points. Young adult offspring from this experiment were resistant to leptin-induced suppression of food intake, body weight loss, and hypothalamic pro-opiomelanocortin (POMC) upregulation. Both male and female BPA-exposed mice showed a reduced density of POMC projections into the paraventricular nucleus of the hypothalamus (PVN). BPA- and DES-exposed pups had respectively delayed and blunted postnatal leptin surges, and POMC projections into the PVN were rescued in female BPA-exposed animals given daily injections of supplemental leptin. Our findings suggest that BPA, a putative obesogen, may exert its effects through developmental programming of the hypothalamic melanocortin circuitry, permanently altering the neurobiology of metabolic homeostasis.

Ghrelin is a peptide hormone involved in multiple physiological processes related to energy homeostasis. This hormone features a unique posttranslational serine octanoylation modification catalyzed by the enzyme ghrelin O-acyltransferase, with serine octanoylation essential for ghrelin to bind and activate its cognate receptor. Ghrelin deacylation rapidly occurs in circulation, with both ghrelin and desacyl ghrelin playing important roles in biological signaling. Understanding the regulation and physiological impact of ghrelin signaling requires the ability to rapidly protect ghrelin from deacylation in biological samples such as blood serum or cell lysates to preserve the relative concentrations of ghrelin and desacyl ghrelin. In in vitro ghrelin O-acyltransferase activity assays using insect microsomal protein fractions and mammalian cell lysate and blood serum, we demonstrate that alkyl fluorophosphonate treatment provides rapid, complete, and long-lasting protection of ghrelin acylation against serine ester hydrolysis without interference in enzyme assay or ELISA analysis. Our results support alkyl fluorophosphonate treatment as a general tool for stabilizing ghrelin and improving measurement of ghrelin and desacyl ghrelin concentrations in biochemical and clinical investigations and suggest current estimates for active ghrelin concentration and the ghrelin to desacyl ghrelin ratio in circulation may underestimate in vivo conditions.

Ghrelin is a 28 amino acid peptide hormone that targets the brain to promote feeding and adiposity. The ghrowth hormone secretagogue receptor 1a (GHSR1a) is expressed within many hypothalamic nuclei, including the ventral premammillary nucleus (PMV), but the role of GHSR1a signaling in this region is unknown. In order to investigate whether GHSR1a signaling within the PMV modulates energy balance, we implanted osmotic minipumps connected to cannulae that were implanted intracranially and aiming at the PMV. The cannulae delivered either saline or ghrelin (10 µg/day at a flow rate of 0.11μL/h for 28 days) into the PMV of adult male C57BLJ6 mice. We found that chronic infusion of ghrelin into the PMV increased weight gain, promoted the oxidation of carbohydrates as a fuel source and resulted in hyperglycemia, without affecting food intake, or body fat. This suggests that ghrelin signaling in the PMV contributes to the modulation of metabolic fuel utilization and glucose homeostasis.

Ghrelin is a 28 amino acid peptide hormone that targets the brain to promote feeding and adiposity. The ghrelin receptor, the GHSR1a, is expressed within most hypothalamic nuclei, including the DMH, but the role of GHSR1a in this region on energy balance is unknown. In order to investigate whether GHSR1a within the DMH modulate energy balance, we implanted osmotic minipumps filled with saline, ghrelin, or the GHSR1a antagonist JMV2959, and connected it to a cannula aimed unilaterally at the DMH of adult male C57BLJ6 mice and assessed their metabolic profile. We found that chronic infusion of ghrelin in the DMH promoted an increase in caloric intake as well as a decrease in energy expenditure. This translated to an overall increase in weight gain, primarily in the form of adipose tissue in ghrelin treated animals. Further, chronic ghrelin unilateral infusion into the DMH slowed glucose clearance. These results suggest that GHSR in the DMH significantly contribute to the metabolic effects produced by ghrelin.

Ghrelin is a hormone associated with feeding and energy balance. Not surprisingly, this hormone is secreted in response to acute stressors and it is chronically elevated after exposure to chronic stress in tandem with a number of metabolic changes aimed at attaining homeostatic balance. In the present review, we propose that ghrelin plays a key role in these stress-induced homeostatic processes. Ghrelin targets the hypothalamus and brain stem nuclei that are part of the sympathetic nervous system to increase appetite and energy expenditure and promote the use of carbohydrates as a source of fuel at the same time as sparing fat. Ghrelin also targets mesolimbic brain regions such as the ventral segmental area and the hippocampus to modulate reward processes, to protect against damage associated with chronic stress, as well as to potentially increase resilience to stress. In all, these data support the notion that ghrelin, similar to corticosterone, is a critical metabolic hormone that is essential for the stress response.

This perspective highlights research presented as part of the symposium entitled, "Stress and Glucocorticoid Modulation of Feeding and Metabolism" at the 2018 Neurobiology of Stress Workshop held in Banff, AB, Canada. The symposium comprised five researchers at different career stages who each study different aspects of the interaction between the stress response and metabolic control. Their collective results reveal the complexity of this relationship in terms of behavioural and physiological outcomes. Their work emphasizes the need to consider the level of interaction (cellular, tissue, systems) as well as the timing and context in which the interaction is studied. Rather than a comprehensive review on the work presented at the Symposium, here we discuss recurring themes that emerged at the biennial workshop, which address new avenues of research that will drive the field forward.

Ghrelin, a peptide hormone associated with appetite, is also linked to increased reward seeking behaviors, including food, sex, and drug seeking behaviors through the stimulation of the mesolimbic dopaminergic system. Moreover, plasma ghrelin concentrations are increased by cues that predict rewards, suggesting that cues could facilitate cravings and ultimately relapse. In this project we examined the effects of an overnight fast, a manipulation known to increase ghrelin concentrations, on gambling behaviors. We also examined if cues associated with gambling would also increase ghrelin and, if so, we examined if these increases were associated with gambling behavior. One hundred and one (37 females) participants were asked to fast overnight or after breakfast and then asked to complete food and gambling craving questionnaires. Participants were then presented with gambling cues (a casino like environment in the lab) or a control cue (a cubicle with a computer). After the cue, subjects filled gambling craving questionnaires, and were allowed to gamble. Following 25 practice spins, the slot machines were fixed so that all subsequent spins were losses, and the number of spins in spite of losses were quantified. Blood samples were collected throughout the experiment. Results showed that the gambling cues significantly increased ghrelin concentrations particularly in fasted individuals, and that ghrelin concentrations 20 min after the cue were the best predictor for gambling persistence in the face of continued loss (p 0.05). Our results suggest that cues that predict the opportunity to gamble have an acute effect on ghrelin concentrations that is facilitated by fasting, and that ghrelin concentrations are a significant predictor of gambling persistence.

Ghrelin, a hormone produced primarily by the stomach, has been associated with motivational processes that include reward-seeking behaviors. In male laboratory mice, elevation of ghrelin levels enhances some aspects of sexual motivation and behavior, whereas in other experiments with male mice, rats, and other species, ghrelin treatment or food deprivation decreases sexual motivation and/or behavior. The present tested the hypothesis that stimulation of ghrelin receptors in different brain regions have opposite effects on male sexual motivation and behavior. To do this we examined appetitive and consummatory sex behaviors of male rats with a truncated ghrelin receptor (FHH-GHSRm1/Mcwi), and that of their WT (FHH) littermates. We also examined the effects of ghrelin or the ghrelin antagonist D-Lys-GHRP6 delivered into the VTA or the MPOA on appetitive and consummatory sex behaviors in male Long Evans rats. Results demonstrate that rats with a truncated ghrelin receptor, or rats that are food deprived, show deficits in anticipatory sex. Furthermore, although ghrelin does not further stimulate sex anticipation in rats when infused into the VTA, intra-VTA infusions of D-Lys-GHRP6 into the VTA further decreases in sex anticipation in food deprived rats. In contrast, ghrelin delivery into the mPOA decreased sex anticipation compared to saline or D-Lys-GHRP6 infused rats. Overall, these data suggest that ghrelin receptor signalling is important for full expression of appetitive sex behaviors. Within the VTA, ghrelin may act to enhance sex motivation, while acting on the mPOA to decrease sex motivation and promote foraging.

Ghrelin is a hormone predominantly produced in and secreted from the stomach. Ghrelin is involved in many physiological processes including feeding, the stress response, and in modulating learning, memory and motivational processes. Ghrelin does this by binding to its receptor, the growth hormone secretagogue receptor (GHSR), a receptor found in relatively high concentrations in hypothalamic and mesolimbic brain regions. While the feeding and metabolic effects of ghrelin can be explained by the effects of this hormone on regions of the brain that have a more permeable blood brain barrier (BBB), ghrelin produced within the periphery demonstrates a limited ability to reach extrahypothalamic regions where GHSRs are expressed. Therefore, one of the most pressing unanswered questions plaguing ghrelin research is how GHSRs, distributed in brain regions protected by the BBB, are activated despite ghrelin's predominant peripheral production and poor ability to transverse the BBB. This manuscript will describe how peripheral ghrelin activates central GHSRs to encourage feeding, and how central ghrelin synthesis and ghrelin independent activation of GHSRs may also contribute to the modulation of feeding behaviours.

Ghrelin, a hormone implicated in the regulation of feeding and energy balance, has also been associated with neural function underlying learning and memory. These effects are thought to be mediated by ghrelin targeting receptors at extra hypothalamic sites such as the hippocampus. Exogenous ghrelin administration increases dendritic spine density in the hippocampal CA1 region and neurogenesis in the dentate gyrus (DG), while improving memory in rats. In the present study, we sought to determine whether rats lacking the ghrelin receptor would show early neural or cognitive decline measured via hippocampal integrity (spine density and neurogenesis) and spatial learning and memory. As such, we used young and middle-aged adult rats with mutations to the gene encoding for the ghrelin receptor (GHS-R KO) and wildtype (WT) littermates to determine differences in performance on hippocampal-dependent tasks (the water maze and radial arm maze). In addition, we examined the hippocampal dentate gyrus of these rats for differences in dendritic spine density and cell proliferation (doublecortin). Overall, results demonstrated that spine density and doublecortin staining in the dentate gyrus of the young GHS-R KO group was similar to that seen in middle-aged groups (both KO and WT) and lower than the young WT group. Middle-aged GHS-R KO and WT groups showed deficits on the radial arm maze food-motivated task but not the water maze task. These data suggest that impaired ghrelin signaling leads to an early onset decrement in hippocampal structural integrity that may manifest in non- spatial-related behavioral deficits.

Negative emotions trigger eating in some individuals (emotional eaters) possibly by influencing stress hormones that contribute to eating regulation (e.g., cortisol), or eating-related peptides (e.g., ghrelin) signaling food initiation. The present study assessed whether stressor-elicited cortisol and ghrelin changes would differ between emotional and non-emotional eaters, and whether eating would influence these neuroendocrine responses. Undergraduate women (N = 103) who completed measures of emotional eating, were assigned to anticipate either a stressful (public speaking) or non-stressful event. During this period, participants were or were not offered food. Blood samples were taken continuously over a 40-min period to assess changes of cortisol and ghrelin levels, and mood was assessed after the anticipation period. Baseline ghrelin levels were lower in emotional than non-emotional eaters, and this relation was mediated by percent body fat. Ghrelin levels were elevated among women anticipating a stressor, compared to those in the control condition. Additionally, the normal decline of ghrelin following food consumption was not apparent among emotional eaters. Although food intake was not tied to hormone responses, reported hunger was associated with greater food intake for women in the stressor condition. It was suggested that emotional eating coupled with subjective feelings of hunger, might contribute to eating in response to an acute stressor. Additionally, feedback mechanisms controlling the normalization of ghrelin levels might be disturbed in emotional eaters. The similarity of the ghrelin profile of emotional eaters to that of binge eaters and obese individuals, raises the possibility that disturbed ghrelin response might be a risk factor for such conditions.

The aim of this study is to analyze how maternal diet during the lactational period influences the adipose tissue response to chronic caloric restriction in offspring. Lactating dams were subjected to one of three treatments: 50% food restriction (FR), ad lib standard chow (AL), or ad lib high-fat diet (HF). Juveniles were first weaned onto standard chow, then in adulthood 50% calorically restricted and maintained at 90% of normal body weight for 60 d. HF animals showed increased percent body fat compared with AL and FR animals despite equivalent body weights. HF animals showed alterations in the balance of adipose tissue lipogenic (FAS, LPL) and lipolytic (HSL) gene expression that may underlie their propensity to maintain fat stores under caloric restriction.

The endocrine disrupting compound bisphenol-A (BPA) has been reported to act as an obesogen in rodents exposed perinatally. In this study, we investigated the effects of early-life BPA exposure on adult metabolic phenotype and hypothalamic energy balance circuitry. Pregnant and lactating CD-1 dams were exposed, via specially prepared diets, to 2 environmentally relevant doses of BPA. Dams consumed an average of 0.19 and 3.49 μg/kg per day of BPA in the low and high BPA treatments prenatally and an average of 0.36 and 7.2 μg/kg per day of BPA postnatally. Offspring were weaned initially onto a normal (AIN93G) diet, then as adults exposed to either a normal or high-fat diet (HFD). Males exposed to the high dose of BPA showed impaired glucose tolerance on both diets. They also showed reduced proopiomelanocortin fiber innervation into the paraventricular nucleus of the hypothalamus, and when exposed to HFD, they demonstrated increased neuropeptide Y and Agouti-related peptide expression in the arcuate nucleus (ARC). Females exposed to the high BPA dose were heavier, ate more, and had increased adiposity and leptin concentrations with reduced proopiomelanocortin mRNA expression in the ARC when consuming a HFD. BPA-exposed females showed ARC estrogen receptor α expression patterns similar to those seen in males, suggesting a masculinizing effect of BPA. These results demonstrate that early-life exposure to the obesogen BPA leads to sexually dimorphic alterations in the structure of hypothalamic energy balance circuitry, leading to increased vulnerability for developing diet-induced obesity and metabolic impairments, such as glucose intolerance.

Chronic stressors promote metabolic disturbances, including obesity and metabolic syndrome. Ghrelin, a peptide that promotes appetite and the accumulation of adipose tissue, is also secreted in response to stressors to protect the brain and peripheral tissues from the effects of these stressors. Here we demonstrate that elevated ghrelin levels produced by chronic exposure to social stress are associated with increased caloric intake and body weight gain in male C57BL mice. In contrast, stressed mice lacking ghrelin receptors (GHSR KO mice) or C57BL mice receiving chronic intracerebroventricular delivery of the ghrelin receptor antagonist [d-Lys3]-GHRP-6 show attenuated weight gain and feeding responses under the same social stress paradigm. Interestingly, stressed GHSR KO mice showed depleted sc and intrascapular brown fat depots, whereas stressed young wild-type mice did not. In old wild-type mice, chronic social defeat increased visceral and intrascapular brown fat depots in association with increases in obesity markers like hyperleptinemia and hyperinsulinemia along with increased hypothalamic expression of neuropeptide Y and Agouti related peptide. Importantly, the elevated expression of these peptides persisted least for 2 weeks after cessation of the stressor regimen. In contrast, old GHSR KO mice did not show these alterations after chronic social defeat. These results suggest that ghrelin plays an important role in the metabolic adaptations necessary to meet the energetic demands posed by stressors, but chronic exposure to stress-induced ghrelin elevations ultimately could lead to long lasting metabolic dysfunctions.

Food restriction has been reported to reduce anxiety-like behaviour in male rats, whereas the effects of food restriction on anxiety in female rats are less clear. Ghrelin is a peptide hormone produced and secreted in the stomach that stimulates food intake and is considered to play a role in reward and emotional responses such as fear expression. Under food restriction, endogenous ghrelin levels increase. In the present study, we examined the effect of moderate food restriction (80% of ad libitum fed weight), with or without an acute application of a small dose of exogenous ghrelin intended to cause an immediate hunger response, on the expression of the acoustic startle reflex (ASR). This was carried out under basal conditions (baseline ASR to 90- and 95-dB noise bursts), and in the presence of a light cue associated with a mild foot-shock, as measured by fear-potentiated startle, which compares the proportional change in ASR in the presence of the conditioned stimulus. The results obtained show that food-restriction reduces basal ASR in both male and female rats, apart from any concomitant change in motor activity, suggesting that food-restriction reduces anxiety levels in both sexes. In addition, the data show that food-restriction reduces fear-potentiated startle in male but not female rats. Acute ghrelin injection, prior to fear-potentiated startle testing, eliminates the expression of fear-potentiated startle in food-restricted male rats alone, suggesting a role for ghrelin in the reduction of fear expression in food-restricted male rats. These data imply that, although food-restriction decreases anxiety in both sexes, learned fear responses remain intact after food-restriction in female but not male rats.

The efficacy of ketamine to alleviate depressive symptoms has promoted a wealth of research exploring alternate therapeutic targets for depression. Given the caveats of ketamine treatment taken together with the increasingly greater emphasis on combinatorial therapeutic approaches to depression, we sought to asses whether the hypothalamic "hunger hormone", ghrelin, would augment the effects of ketamine. Indeed, ghrelin has recently been found to possess antidepressant potential and may be especially effective against the metabolic and feeding deficits observed with depression. Two studies were performed: 1. mice were given an intraperitoneal injection of ghrelin (80μg/kg) or saline, followed by a saline or a low or high dose of ketamine (5 or 10mg/kg) and 2. mice received 10mg/kg of ketamine together with saline or the ghrelin receptor antagonist JMV2959 (3 or 6mg/kg) and Forced Swim Test (FST) performance was assessed. In both studies, ketamine alone reduced FST immobility. Similarly, ghrelin alone reduced swim immobility suggesting an antidepressant-like response. However, ghrelin did not augment the impact of ketamine when co-administered and in fact, it appeared to antagonize its actions at the lower dose. As well, JMV2959 did not significantly influence FST performance. These data confirm the antidepressant-like effects of ketamine and further suggest that ghrelin might have similar properties. Yet, our results caution against combinatorial treatment with these agents, probably owing to unexpected allosteric or other antagonist actions.

Ghrelin, a circulating gut-hormone, has emerged as an important regulator of growth hormone release and appetite. Ghrelin-immunopositive neurons have also been identified in the hypothalamus with a unique anatomical distribution. Here, we report that ghrelin-labeled neurons receive direct synaptic input from the suprachiasmatic nucleus, the central circadian timekeeper of the brain, and lateral geniculate nucleus, a visual center, and project synaptically to the lateral hypothalamic orexin/hypocretin system, a region of the brain critical for arousal. Hypothalamic ghrelin mRNA oscillates in a circadian pattern peaking in the dark phase prior to the switch from arousal to sleep. Ghrelin inhibits the electrophysiological activity of identified orexin/hypocretin neurons in hypothalamic slices. These observations indicate that the hypothalamic neurons identified by ghrelin immunolabeling may be a key mediator of circadian and visual cues for the hypothalamic arousal system.

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.

Ghrelin is an orexigenic stomach peptide previously found to be important for the full display of anticipatory locomotor activity and hypothalamic neuronal activation that precedes a daily scheduled meal in mice. Ghrelin is also important for food-related motivation and seems to have direct effects in the mesocorticolimbic dopamine reward system. Here we hypothesized that neuronal activation in reward-related areas in anticipation of a scheduled meal could be mediated by elevated ghrelin induced by scheduled feeding, and therefore this would be attenuated in ghrelin receptor knock-out (GHSR KO) animals. We found that this was indeed the case for the ventral tegmental area and the shell, but not the core, of the nucleus accumbens. In addition, our results show a reduction in the proportion of activated orexin-immunoreactive (IR) neurons in GHSR KO animals in anticipation of the scheduled meal in comparison to the proportion of activated orexin neurons in wild type (WT) mice. Interestingly we observed that both GHSR and ghrelin KO mice had fewer orexin-IR cells than their WT littermates suggesting that lack of ghrelin or sensitivity to ghrelin may play a role in the development of the orexin system. Our data also suggest that ghrelin may mediate food anticipation, in part, by stimulating both the orexin system and the mesolimbic reward system.

Ghrelin was discovered in 1999 as growth hormone secretagouge released from the gut. Soon after it was recognized that ghrelin is a fundamental driver of appetite in rodents and humans and that its mode of action requires alteration of hypothalamic circuit function. Here we review aspects of ghrelin's action that revolve around the central nervous system with the goal to highlight these pathways in integrative physiology of metabolism regulation including ghrelin's cross-talk with the action of the adipose hormone, leptin.