Stress-induced Hypophagia Research Articles

Feedforward inhibition of stress by brainstem neuropeptide Y neurons

Resistance to stress is a key determinant for mammalian functioning. While many studies have revealed neural circuits and substrates responsible for initiating and mediating stress responses, little is known about how the brain resists to stress and prevents overreactions. Here, we identified a previously uncharacterized neuropeptide Y (NPY) neuronal population in the dorsal raphe nucleus and ventrolateral periaqueductal gray region (DRN/vlPAG) with anxiolytic effects in male mice. NPYDRN/vlPAG neurons are rapidly activated by various stressful stimuli. Inhibiting these neurons exacerbated hypophagic and anxiety responses during stress, while activation significantly ameliorates acute stress-induced hypophagia and anxiety levels and transmits positive valence. Furthermore, NPYDRN/vlPAG neurons exert differential but synergic anxiolytic effects via inhibitory projections to the paraventricular thalamic nucleus (PVT) and the lateral hypothalamic area (LH). Together, our findings reveal a feedforward inhibition neural mechanism underlying stress resistance and suggest NPYDRN/vlPAG neurons as a potential therapeutic target for stress-related disorders.

High fat diet blunts stress-induced hypophagia and activation of Glp1r dorsal lateral septum neurons in male but not in female mice

ObjectiveWhile stress typically reduces caloric intake (hypophagia) in chow-fed rodents, presentation of palatable, high calorie substances during stress can increase caloric consumption (i.e. “comfort feeding”) and promote obesity. However, little is known about how obesity itself affects feeding behavior in response to stress and the mechanisms that can influence stress-associated feeding in the context of obesity. MethodsWe assessed food intake and other metabolic parameters in lean and obese male and female mice following acute restraint stress. We also measured real-time activity of glucagon-like peptide-1 (Glp1) receptor (Glp1r)-expressing neurons in the dorsal lateral septum (dLS) during stress in lean and obese mice using fiber photometry. Glp1r activation in various brain regions, including the dLS, promotes hypophagia in response to stress. Finally, we used inhibitory Designer Receptors Activated Exclusively by Designer Drugs (DREADDs) to test whether activation of Glp1r-expressing neurons in the LS is required for stress-induced hypophagia. ResultsLean male mice display the expected hypophagic response following acute restraint stress, but obese male mice are resistant to this acute stress-induced hypophagia. Glp1r-positive neurons in the dLS are robustly activated during acute restraint stress in lean but not in obese male mice. This raises the possibility that activation of dLS Glp1r neurons during restraint stress contributes to subsequent hypophagia. Supporting this, we show that chemogenetic inhibition of LS Glp1r neurons attenuates acute restraint stress hypophagia in male mice. Surprisingly, we show that both lean and obese female mice are resistant to acute restraint stress-induced hypophagia and activation of dLS Glp1r neurons. ConclusionsThese results suggest that dLS Glp1r neurons contribute to the hypophagic response to acute restraint stress in male mice, but not in female mice, and that obesity disrupts this response in male mice. Broadly, these findings show sexually dimorphic mechanisms and feeding behaviors in lean vs. obese mice in response to acute stress.

Acute Stress Exposure Alters Food-Related Brain Monoaminergic Profiles in a Rat Model of Anorexia

BackgroundAdverse life experiences are a major risk factor for anorexia nervosa (AN). Eating-provoked anxiousness associated with AN is postulated to be due to food-related exaggerated serotonin activity in the brain and imbalances of monoamine neurotransmitters. ObjectivesUsing a rodent model of stress-induced hypophagia, we investigated if stress exposure augments food-related serotonin turnover and imbalances in measures of brain serotonin and dopamine activity in manners consistent with anxiousness toward food and restricted eating. MethodsAdult male F344 rats were conditioned to associate an audio cue with daily food over 2 weeks, after which half of the rats were exposed to a single episode of tail shocks (stress) or left undisturbed (nonstressed). All rats were killed 48 h later, during a control period, the food-associated cue, or a period of food access. Serotonin, dopamine, and norepinephrine, as well as metabolite concentrations, were assessed across brain regions comprising reward, emotion, and feeding circuits relevant to AN in acutely stressed and nonstressed rats using HPLC. Statistical significance level was 5%. ResultsStress-induced rat hypophagia paralleled an augmented serotonin turnover in response to the food-associated cue in the hypothalamus and hippocampus, as well as food access in the hypothalamus and cortical areas (all P < 0.05). Stress exposure increased the ratio of serotonin to dopamine metabolites across several brain areas, but the magnitude of this imbalance was further augmented during the food-associated cue and food access in the brainstem, hippocampus, and cortical areas (all P < 0.05). Finally, stress lowered norepinephrine concentrations by 18% in the hypothalamus (P < 0.05). ConclusionsThe observed stress-induced changes to monoamine profiles in rats could have key implications for physiological states that contribute to restricted eating and may hold relevance for the development of AN precipitated by adverse life experiences.

Effects of endocannabinoids on feed intake, stress response and whole-body energy metabolism in dairy cows

Endocannabinoids, particularly anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are instrumental in regulating energy homeostasis and stress response. However, little is known about the endocannabinoid system (ECS) in ruminants, although EC could improve dairy health and productivity, at least by increasing feed intake. In this study, we report if intraperitoneal (i.p.) AEA and 2-AG administration affects feed intake, whole-body macronutrient metabolism, isolation and restraint stress, and whether diet composition modulates circulating endocannabinoid concentrations in cows. Twenty Simmental cows in late lactation were fed a grass silage and a corn silage based diet. On each diet, cows received daily i.p. injections with either AEA (5 µg/kg; n = 7), 2-AG (2.5 µg/kg; n = 6) or saline (n = 7) for 8 days. Endocannabinoid administration for 5 days under free-ranging (non-stressed) conditions had no effect on feed intake or energy balance, but attenuated the stress-induced suppression of feed intake when housing changed to individual tie-stalls without social or tactile interaction. Endocannabinoids increased whole-body carbohydrate oxidation, reduced fat oxidation, and affected plasma non-esterified fatty acid concentrations and fatty acid contents of total lipids. There was no effect of endocannabinoids on plasma triglyceride concentrations or hepatic lipogenesis. Plasma AEA concentrations were not affected by diet, however, plasma 2-AG concentrations tended to be lower on the corn silage based diet. In conclusion, endocannabinoids attenuate stress-induced hypophagia, increase short-term feed intake and whole-body carbohydrate oxidation and decrease whole-body fat oxidation in cows.

The diverse effects of brain glucagon‐like peptide 1 receptors on ingestive behaviour

Glucagon-like peptide 1 (GLP-1) is well known as a gut hormone and also acts as a neuropeptide, produced in a discrete population of caudal brainstem neurons that project widely throughout the brain. GLP-1 receptors are expressed in many brain areas of relevance to energy balance, and stimulation of these receptors at many of these sites potently suppresses food intake. This review surveys the current evidence for effects mediated by GLP-1 receptors on feeding behaviour at a wide array of brain sites and discusses behavioural and neurophysiological mechanisms for the effects identified thus far. Taken together, it is clear that GLP-1 receptor activity in the brain can influence feeding by diverse means, including mediation of gastrointestinal satiation and/or satiety signalling, suppression of motivation for food reward, induction of nausea and mediation of restraint stress-induced hypophagia, but many questions about the organization of this system remain.

Oxytocin activation of paraventricular thalamic neurons promotes feeding motivation to attenuate stress-induced hypophagia.

The neuropeptide oxytocin (OT) regulates important brain functions including feeding through activating OT receptors in multiple brain areas. Both OT fibers and OT receptors have been reported in the paraventricular thalamus (PVT), an area that was revealed to be important for the control of emotion, motivation, and food intake. However, the function and modulation of PVT OT signaling remain unknown. Here, we used a progressive ratio (PR) schedule of reinforcement to examine the role of PVT OT signaling in regulating the motivation for food and patch-clamp electrophysiology to study the modulation of OT on PVT neurons in brain slices. We demonstrate that PVT OT administration increases active lever presses to earn food rewards in both male and female mice under PR trials and OT receptor antagonist atosiban inhibits OT-induced increase in motivated lever presses. However, intra-PVT OT infusion does not affect food intake in normal conditions but attenuates hypophagia induced by stress and anxiety. Using patch-clamp recordings, we find OT induces long-lasting excitatory effects on neurons in all PVT regions, especially the middle to posterior PVT. OT not only evokes tonic inward currents but also increases the frequency of spontaneous excitatory postsynaptic currents on PVT neurons. The excitatory effect of OT on PVT neurons is mimicked by the specific OT receptor agonist [Thr4, Gly7]-oxytocin (TGOT) and blocked by OT receptor antagonist atosiban. Together, our study reveals a critical role of PVT OT signaling in promoting feeding motivation to attenuate stress-induced hypophagia through exciting PVT neurons.

A POMC-originated circuit regulates stress-induced hypophagia, depression, and anhedonia.

Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DAVTA neurons). We further revealed that POMCARH neurons project to the VTA and provide an inhibitory tone to DAVTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMCARH→VTA circuit in mice increases body weight and food intake, and reduces depression-like behaviors and anhedonia in mice exposed to chronic restraint stress. Thus, our results identified a novel neurocircuitry regulating feeding and mood in response to stress.

Endogenous GLP-1 in lateral septum promotes satiety and suppresses motivation for food in mice

Glucagon-like peptide 1 receptors (GLP-1R) are expressed in the lateral septum (LS) of rats and mice, and we have published that endogenous LS GLP-1 affects feeding and motivation for food in rats. Here we asked if these effects are also observed in mice. In separate dose-response studies using male C57Bl6J mice, intra-LS GLP-1 or the GLP-1R antagonist Exendin 9 (Ex9) was delivered shortly before dark onset, at doses subthreshold for effect when injected intracerebroventricularly (icv). Intra-LS GLP-1 significantly suppressed chow intake early in the dark phase and tended to reduce overnight intake. However, blockade of LS GLP-1R with Ex9 had no effect on ad libitum dark onset chow intake. We then asked if LS GLP-1R blockade blunts nutrient preload-induced intake suppression. Mice were trained to consume Ensure immediately before dark onset, which suppressed subsequent chow intake, and intra-LS Ex9 attenuated that preload-induced intake suppression. We also found that restraint stress robustly activates hindbrain GLP-1-producing neurons, and that LS GLP-1R blockade attenuates 30-min restraint stress-induced hypophagia in mice. Furthermore, we have reported that in the rat, GLP-1R in the dorsal subregion of the LS (dLS) affect motivation for food. We examined this in food-restricted mice responding for sucrose pellets on a progressive ratio (PR) schedule. Intra-dLS GLP-1R stimulation significantly suppressed, and Ex9 significantly increased, operant responding, and the Ex9 effect remained after mice returned to ad libitum conditions. Similarly, we found that stimulation of dLS GLP-1 suppressed licking for sucrose and conversely, Ex9 increased licking under ad libitum feeding conditions. Together, our data suggest that endogenous activation of LS GLP-1R plays a role in feeding in mice under some but not all conditions, and that these receptors strongly influence motivation for food.

Chronic Suppression of Glucagon-Like Peptide-1 Receptor (GLP1R) mRNA Translation in the Rat Bed Nucleus of the Stria Terminalis Reduces Anxiety-Like Behavior and Stress-Induced Hypophagia, But Prolongs Stress-Induced Elevation of Plasma Corticosterone.

The anterior lateral bed nucleus of the stria terminalis (alBST) expresses glucagon-like peptide-1 receptors (GLP1Rs) and receives input from caudal brainstem GLP1 neurons. GLP1 administered centrally reduces food intake and increases anxiety-like behavior and plasma corticosterone (cort) levels in rats, whereas central GLP1R antagonism has opposite effects. Anxiogenic threats and other stressors robustly activate c-fos expression in both GLP1-producing neurons and also in neurons within alBST subregions expressing GLP1R. To examine the functional role of GLP1R signaling within the alBST, adult male Sprague Dawley rats received bilateral alBST-targeted injections of an adeno-associated virus (AAV) vector expressing short hairpin RNA (shRNA) to knock down the translation of GLP1R mRNA (GLP1R-KD rats), or similar injections of a control AAV (CTRL rats). In situ hybridization revealed that GLP1R mRNA is expressed in a subset of GABAergic alBST neurons, and quantitative real-time PCR confirmed that GLP1R-KD rats displayed a significant 60% reduction in translatable GLP1R mRNA. Compared with CTRL rats, GLP1R-KD rats gained more body weight over time and displayed less anxiety-like behavior, including a loss of light-enhanced acoustic startle and less stress-induced hypophagia. Conversely, while baseline plasma cort levels were similar in GLP1R-KD and CTRL rats, GLP1R-KD rats displayed a prolonged stress-induced elevation of plasma cort levels. GLP1R-KD and CTRL rats displayed similar home cage food intake and a similar hypophagic response to systemic Exendin-4, a GLP1R agonist that crosses the blood-brain barrier. We conclude that GLP1R expressed within the alBST contributes to multiple behavioral responses to anxiogenic threats, yet also serves to limit the plasma cort response to acute stress.SIGNIFICANCE STATEMENT Anxiety is an affective and physiological state that supports threat avoidance. Identifying the neural bases of anxiety-like behaviors in animal models is essential for understanding mechanisms that contribute to normative and pathological anxiety in humans. In rats, anxiety/avoidance behaviors can be elicited or enhanced by visceral or cognitive threats that increase glucagon-like peptide-1 (GLP1) signaling from the caudal brainstem to the hypothalamus and limbic forebrain. Data reported here support a role for limbic GLP1 receptor signaling to enhance anxiety-like behavior and to attenuate stress-induced elevations in plasma cort levels in rats. Improved understanding of central GLP1 neural pathways that impact emotional responses to stress could expand potential therapeutic options for anxiety and other stress-related disorders in humans.

Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food.

Centrally administered glucagon-like peptide 1 (GLP-1) supresses food intake. Here we demonstrate that GLP-1-producing (PPG) neurons in the nucleus tractus solitarii (NTS) are the predominant source of endogenous GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A substantially reduced active GLP-1 concentrations in brain and spinal cord. Contrary to expectations, this loss of central GLP-1 had no significant effect on the ad libitum feeding of mice, affecting neither daily chow intake nor body weight or glucose tolerance. Only after bigger challenges to homeostasis were PPG neurons necessary for food intake control. PPG-ablated mice increased food intake after a prolonged fast and after a liquid diet preload. Consistent with our ablation data, acute inhibition of hM4Di-expressing PPG neurons did not affect ad libitum feeding; however, it increased refeeding intake after fast and blocked stress-induced hypophagia. Additionally, chemogenetic PPG neuron activation through hM3Dq caused a strong acute anorectic effect. We conclude that PPG neurons are not involved in primary intake regulation but form part of a secondary satiation/satiety circuit, which is activated by both psychogenic stress and large meals. Given their hypophagic capacity, PPG neurons might be an attractive drug target in obesity treatment.

Endogenous GLP-1 in lateral septum contributes to stress-induced hypophagia.

Glucagon-like peptide 1 (GLP-1) neurons of the caudal brainstem project to many brain areas, including the lateral septum (LS), which has a known role in stress responses. Previously, we showed that endogenous GLP-1 in the LS plays a physiologic role in the control of feeding under non-stressed conditions, however, central GLP-1 is also involved in behavioral and endocrine responses to stress. Here, we asked whether LS GLP-1 receptors (GLP-1R) contribute to stress-induced hypophagia. Male rats were implanted with bilateral cannulas targeting the dorsal subregion of the LS (dLS). In a within-subjects design, shortly before the onset of the dark phase, rats received dLS injections of saline or the GLP-1R antagonist Exendin (9-39) (Ex9) prior to 30 min restraint stress. Food intake was measured continuously for the next 20 h. The stress-induced hypophagia observed within the first 30 min of dark was not influenced by Ex9 pretreatment, but Ex9 tended to blunt the effect of stress as early as 1 and 2 h into the dark phase. By 4-6 h, there were significant stress X drug interactions, and Ex9 pretreatment blocked the stress-induced suppression of feeding. These effects were mediated entirely through changes in average meal size; stress suppressed meal size while dLS Ex9 attenuated this effect. Using a similar design, we examined the role of dLS GLP-1R in the neuroendocrine response to acute restraint stress. As expected, stress potently increased serum corticosterone, but blockade of dLS GLP-1Rs did not affect this response. Together, these data show that endogenous GLP-1 action in the dLS plays a role in some but not all of the physiologic responses to acute stress.

GLP-1 action in the mouse bed nucleus of the stria terminalis

Glucagon-like peptide-1 (GLP-1) injected into the brain reduces food intake. Similarly, activation of preproglucagon (PPG) cells in the hindbrain which synthesize GLP-1, reduces food intake. However, it is far from clear whether this happens because of satiety, nausea, reduced reward, or even stress. Here we explore the role of the bed nucleus of the stria terminalis (BNST), an area involved in feeding control as well as stress responses, in GLP-1 responses.Using cre-expressing mice we visualized projections of NTS PPG neurons and GLP-1R-expressing BNST cells with AAV-driven Channelrhodopsin-YFP expression. The BNST displayed many varicose YFP+ PPG axons in the ventral and less in the dorsal regions. Mice which express RFP in GLP-1R neurons had RFP+ cells throughout the BNST with the highest density in the dorsal part, suggesting that PPG neuron-derived GLP-1 acts in the BNST. Indeed, injection of GLP-1 into the BNST reduced chow intake during the dark phase, whereas injection of the GLP-1 receptor antagonist Ex9 increased feeding. BNST-specific GLP-1-induced food suppression was less effective in mice on high fat (HF, 60%) diet, and Ex9 had no effect. Restraint stress-induced hypophagia was attenuated by BNST Ex9 treatment, further supporting a role for endogenous brain GLP-1. Finally, whole-cell patch clamp recordings of RFP+ BNST neurons demonstrated that GLP-1 elicited either a depolarizing or hyperpolarizing reversible response that was of opposite polarity to that under dopamine.Our data support a physiological role for BNST GLP-1R in feeding, and suggest complex cellular responses to GLP-1 in this nucleus.

Adaptive Control of Dorsal Raphe by 5-HT4 in the Prefrontal Cortex Prevents Persistent Hypophagia following Stress

Transient reduced food intake (hypophagia) following high stress could have beneficial effects on longevity, but paradoxically, hypophagia can persist and become anorexia-like behavior. The neural underpinnings of stress-induced hypophagia and the mechanisms by which the brain prevents the transition from transient to persistent hypophagia remain undetermined. In this study, we report the involvement of anetwork governing goal-directed behavior (decision). This network consists of the ascending serotonergic inputs from the dorsal raphenucleus (DR) to the medial prefrontal cortex (mPFC).Specifically, adult restoration of serotonin 4 receptor (5-HT4R) expression in the mPFC rescues hypophagia and specific molecular changes related to depression resistance in the DR (5-HT release elevation, 5-HT1A receptor, and 5-HT transporter reductions) of stressed 5-HT4R knockout mice. Theadult mPFC-5-HT4R knockdown mimics the null phenotypes. When mPFC-5-HT4Rs are overexpressed and DR-5-HT1ARs are blocked in the DR, hypophagia following stress persists, suggesting an antidepressant action of early anorexia.

Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse

We measured serum CORT elevation in wild-type and PACAP-deficient C57BL/6N male mice after acute (1 h) or prolonged (2–3 h) daily restraint stress for 7 d. The PACAP dependence of CORT elevation was compared to that of stress-induced hypophagia. Daily restraint induced unhabituated peak CORT elevation, and hypophagia/weight loss, of similar magnitude for 1, 2, and 3 h of daily restraint, in wild-type mice. Peak CORT elevation, and hypophagia, were both attenuated in PACAP-deficient mice for 2 and 3 h daily restraint. Hypophagia induced by 1-h daily restraint was also greatly reduced in PACAP-deficient mice, however CORT elevation, both peak and during recovery from stress, was unaffected. Thus, hypothalamic PACAPergic neurotransmission appears to affect CRH gene transcription and peptide production, but not CRH release, in response to psychogenic stress. A single exposure to restraint sufficed to trigger hypophagia over the following 24 h. PACAP deficiency attenuated HPA axis response (CORT elevation) to prolonged (3 h) but not acute (1 h) single-exposure restraint stress, while hypophagia induced by either a single 1 h or a single 3 h restraint were both abolished in PACAP-deficient mice. These results suggest that PACAP’s actions to promote suppression of food intake following an episode of psychogenic stress is unrelated to the release of CRH into the portal circulation to activate the pituitary-adrenal axis. Furthermore, demonstration of suppressed food intake after a single 1-h restraint stress provides a convenient assay for investigating the location of the synapses and circuits mediating the effects of PACAP on the behavioral sequelae of psychogenic stress.

Hindbrain glucagon-like peptide-1 neurons track intake volume and contribute to injection stress-induced hypophagia in meal-entrained rats.

Published research supports a role for central glucagon-like peptide 1 (GLP-1) signaling in suppressing food intake in rodent species. However, it is unclear whether GLP-1 neurons track food intake and contribute to satiety, and/or whether GLP-1 signaling contributes to stress-induced hypophagia. To examine whether GLP-1 neurons track intake volume, rats were trained to consume liquid diet (LD) for 1 h daily until baseline intake stabilized. On test day, schedule-fed rats consumed unrestricted or limited volumes of LD or unrestricted volumes of diluted (calorically matched to LD) or undiluted Ensure. Rats were perfused after the test meal, and brains processed for immunolocalization of cFos and GLP-1. The large majority of GLP-1 neurons expressed cFos in rats that consumed satiating volumes, regardless of diet type, with GLP-1 activation proportional to intake volume. Since GLP-1 signaling may limit intake only when such large proportions of GLP-1 neurons are activated, a second experiment examined the effect of central GLP-1 receptor (R) antagonism on 2 h intake in schedule-fed rats. Compared with baseline, intracerebroventricular vehicle (saline) suppressed Ensure intake by ∼11%. Conversely, intracerebroventricular injection of vehicle containing GLP-1R antagonist increased intake by ∼14% compared with baseline, partly due to larger second meals. We conclude that GLP-1 neural activation effectively tracks liquid diet intake, that intracerebroventricular injection suppresses intake, and that central GLP-1 signaling contributes to this hypophagic effect. GLP-1 signaling also may contribute to satiety after large volumes have been consumed, but this potential role is difficult to separate from a role in the hypophagic response to intracerebroventricular injection.

Serotonin 2C receptor contributes to gender differences in stress-induced hypophagia in aged mice

The combination of depression and anorexia may influence morbidity and progressive physical disability in the elderly. Gender differences exist in hypothalamic-pituitary-adrenal axis activation following stress exposure. The objective of this study was to investigate gender differences in feeding behavior under novelty stress in aged mice. Food intake measurement, immunohistochemical assessment, and mRNA expression analysis were conducted to investigate the role of serotonin 2C receptor (5-HT(2C)R) and its relationship with ghrelin in stress-induced suppression of feeding behavior in aged mice. After exposure to novelty stress, a 21-fold increase in plasma corticosterone and remarkable suppression of food intake were observed in aged male mice. Furthermore, a 5-HT(2C)R agonist suppressed food intake in aged male mice. Novelty stress induced a 7-fold increase in 5-HT(2C)R and c-Fos co-expressing cells in the paraventricular nucleus of the hypothalamus in aged male mice but caused no change in aged female mice. Plasma acylated ghrelin levels decreased in stressed aged male mice and administration of the 5-HT(2C)R antagonist inhibited this decrease. The 5-HT(2C)R antagonist also reversed the suppression of food intake in estrogen receptor α agonist-treated aged male mice. Therefore, conspicuously suppressed feeding behavior in novelty stress-exposed aged male mice may be mediated by 5-HT(2C)R hypersensitivity, leading to hypoghrelinemia. The hypersensitivity may partly be due to estrogen receptor activation in aged male mice.

Satiation and stress-induced hypophagia: examining the role of hindbrain neurons expressing prolactin-releasing Peptide or glucagon-like Peptide 1.

Neural circuits distributed within the brainstem, hypothalamus, and limbic forebrain interact to control food intake and energy balance under normal day-to-day conditions, and in response to stressful conditions under which homeostasis is threatened. Experimental studies using rats and mice have generated a voluminous literature regarding the functional organization of circuits that inhibit food intake in response to satiety signals, and in response to stress. Although the central neural bases of satiation and stress-induced hypophagia often are studied and discussed as if they were distinct, we propose that both behavioral states are generated, at least in part, by recruitment of two separate but intermingled groups of caudal hindbrain neurons. One group comprises a subpopulation of noradrenergic (NA) neurons within the caudal nucleus of the solitary tract (cNST; A2 cell group) that is immunopositive for prolactin-releasing peptide (PrRP). The second group comprises non-adrenergic neurons within the cNST and nearby reticular formation that synthesize glucagon-like peptide 1 (GLP-1). Axonal projections from PrRP and GLP-1 neurons target distributed brainstem and forebrain regions that shape behavioral, autonomic, and endocrine responses to actual or anticipated homeostatic challenge, including the challenge of food intake. Evidence reviewed in this article supports the view that hindbrain PrRP and GLP-1 neurons contribute importantly to satiation and stress-induced hypophagia by modulating the activity of caudal brainstem circuits that control food intake. Hindbrain PrRP and GLP-1 neurons also engage hypothalamic and limbic forebrain networks that drive parallel behavioral and endocrine functions related to food intake and homeostatic challenge, and modulate conditioned and motivational aspects of food intake.

Rikkunshito and Ghrelin Secretion

Rikkunshito is a kampo herbal medicine which is widely used in Japan for the treatment of the upper gastrointestinal symptoms of patients with functional dyspepsia (FD), gastroesophageal reflux disease (GERD), dyspeptic symptoms of postgastrointestinal surgery patients, and chemotherapy-induced dyspepsia in cancer patients. Recently, very unique characteristics of rikkunshito have been unveiled; oral administration of rikkunshito potentiates orexigenic action of ghrelin through several different mechanisms. In addition, several lines of evidence obtained from both animal and human studies indicate that rikkunshito can be an attractive and promising therapeutic option for the anorectic conditions including cisplatin-induced dyspepsia, anorexia of aging, stress-induced hypophagia, cancer cachexia-anorexia syndrome. In this review, we will highlight what is known about the orexigenic effect of rikkunshito with a special focus on an interaction with ghrelin signaling system.

Intermittent access to sucrose increases sucrose-licking activity and attenuates restraint stress-induced activation of the lateral septum

Intermittent access to palatable food can attenuate anorectic and hormonal responses to stress in rats. The neuronal mechanisms of modulation of stress response by diets are not fully understood. The present study was conducted to create rat models with intermittent access to sucrose that demonstrate resistance to stress-induced hypophagia, to study the pattern of sucrose consumption by these rat models, and to investigate in which brain structures intermittent sucrose regimens modify stress-induced neuronal activation. The obtained results demonstrate that 6-wk intermittent access to sucrose without food restriction (4 day/wk ad libitum access to sucrose in addition to chow, and following 3 day/wk exclusive feeding of chow; SIA rats) and combined with food restriction (4 day/wk access to chow and sucrose restricted to 2 h/day, and following 3 days/wk on unrestricted chow; SIR rats) increased sucrose-licking activity. The alterations in the rats' feeding behavior were accompanied by a resistance of their body weight gain and food intake to 1-h restraint stress applied once per week. The chronic intermittent sucrose consumption significantly lowered, in the SIA and SIR rats, the levels of expression of corticotropin-releasing factor type 2 receptor and restraint stress-induced expression of c-fos mRNA in the medioventral part of the lateral septum. Conversely, the levels of the corticotropin-releasing factor type 2 receptor transcript in the ventromedial hypothalamic nucleus were decreased only in the food-restricted SIR rats. The lower stress-induced neuronal activation in the medioventral part of the lateral septum may contribute to the attenuated anorectic stress response in the rats maintained on intermittent sucrose regimens.

The melanocortin system as a central integrator of direct and indirect controls of food intake

the neural control of food intake and body weight is a complex function in which cognitive and emotional variables, as well as long-term signals of metabolic status and fuel storage, are integrated with short-term signals related to individual meals. Several years ago, Smith ([20][1]) proposed a