Regulation Of Ingestive Behavior Research Articles

Deletion of the Cold Thermoreceptor TRPM8 Increases Heat Loss and Food Intake Leading to Reduced Body Temperature and Obesity in Mice.

The coupling of energy homeostasis to thermoregulation is essential to maintain homeothermy in changing external environments. We studied the role of the cold thermoreceptor TRPM8 in this interplay in mice of both sexes. We demonstrate that TRPM8 is required for a precise thermoregulation in response to cold, in fed and fasting. Trpm8-/- mice exhibited a fall of 0.7°C in core body temperature when housed at cold temperatures, and a deep hypothermia (<30°C) during food deprivation. In both situations, TRPM8 deficiency induced an increase in tail heat loss. This, together with the presence of TRPM8-sensory fibers innervating the main tail vessels, unveils a major role of this ion channel in tail vasomotor regulation. Finally, TRPM8 deficiency had a remarkable impact on energy balance. Trpm8-/- mice raised at mild cold temperatures developed late-onset obesity and metabolic dysfunction, with daytime hyperphagia and reduction of fat oxidation as plausible causal factors. In conclusion, TRPM8 fine-tunes eating behavior and fuel utilization during thermoregulatory adjustments to mild cold. Persistent imbalances in these responses result in obesity.SIGNIFICANCE STATEMENT The thermosensitive ion channel TRPM8 is required for a precise thermoregulatory response to cold and fasting, playing an important role in tail vasoconstriction, and therefore heat conservation, as well as in the regulation of ingestive behavior and metabolic fuel selection upon cooling. Indeed, TRPM8-deficient mice, housed in a mild cold environment, displayed an increase in tail heat loss and lower core body temperature, associated with the development of late-onset obesity with glucose and lipid metabolic dysfunction. A persistent diurnal hyperphagia and reduced fat oxidation constitute plausible underlying mechanisms in the background of a deficient thermoregulatory adjustment to mild cold ambient temperatures.

Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetite.

Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT2CR) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT2CR in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT2CR regulated appetite in a genotypically relevant PWS mouse model (PWS-IC). Specifically, we demonstrate that loss of Snord115 expression is associated with increased levels of hypothalamic truncated 5-HT2CR pre-mRNA. The 5-HT2CR promotes appetite suppression via engagement of the central melanocortin system. Pro-opiomelancortin (Pomc) mRNA levels within the arcuate nucleus of the hypothalamus (ARC) were reduced in PWS-IC mice. We then went on to assess the functional consequences of these molecular changes, demonstrating that PWS-IC mice are unresponsive to an anorectic doses of a 5-HT2CR agonist and that this is associated with attenuated activation of POMC neurons within the ARC. These data provide new insight into the significance of Htr2c pre-mRNA processing to the physiological regulation of appetite and potentially the pathological manifestation of hyperphagia in PWS. Furthermore, these findings have translational relevance for individuals with PWS who may seek to control appetite with another 5-HT2CR agonist, the new obesity treatment lorcaserin.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0277-4) contains supplementary material, which is available to authorized users.

The opioid system contributes to the acquisition of reinforcement for dietary fat but is not required for its maintenance

The opioid system plays an important role in ingestive behavior, especially with regard to palatable high-fat or sweetened foods. In the present study, we investigated the role of the opioid system in the regulation of ingestive behavior in mice with regard to dietary fat intake, reinforcement, and particularly the processes involved in development of these behavior types. Subcutaneous administration of the non-selective opioid receptor antagonist naltrexone (0.5 or 2.0mg/kg body weight [BW]) reduced the spontaneous intake of fat emulsion (Intralipid). We investigated the effect of naltrexone on reinforcement by using an operant behavioral paradigm under a progressive ratio schedule in which the number of lever presses required to obtain a test sample increased progressively. Mice showed stronger reinforcement by Intralipid as a function of concentration. However, naltrexone (0.5 or 2.0mg/kg BW) did not affect reinforcement at any concentration of Intralipid in mice that had repeatedly ingested Intralipid before testing was carried out. Intralipid ingestion also induced conditioned place preference (CPP), which is another evaluation index of reinforcement. High-dose naltrexone (2.0mg/kg BW) administration during CPP conditioning suppressed the reinforcement induced by Intralipid ingestion, although the drug administration (0.5 or 2.0mg/kg BW) during CPP testing did not affect reinforced behavior. These results suggest that the amount of fat ingestion and reinforcement for fat ingestion are separately regulated by the opioid system. Furthermore, our results indicate that the opioid system plays an important role in acquiring reinforcement for fat but is not required for maintenance of learned reinforcement.

Physiological and pathophysiological signalling between the gut and the kidney: role in diabetic kidney disease.

Physiological and pathophysiological signalling between the gut and the kidney: role in diabetic kidney disease.

Assessment of the interaction of progesterone and estrogen administered intraperitoneally on food intake, water intake and body weight in ovariectomized albino rats

Background and Aim: The gonadal hormones like estrogen and progesterone play important role in the regulation of ingestive behaviors and body weight. Recent report from our laboratory indicates the inhibitory role of intraperitoneally injected estrogen on food intake in rats. However, the reports of progesterone, the other important female gonadal hormone on ingestive behaviors are not clearly elucidated. Moreover, the interaction of progesterone with estrogen in mediating ingestive behaviors is also not clear. Therefore in the present study, we have assessed the effects of progesterone injected alone and in combination with estrogen on ingestive behaviors and body weight in ovariectomized albino rats. Methods: Bilateral ovariectomy was performed in 24 rats, and postovariectomy basal food and water intake and body weight were recorded. The animals were divided into two groups: progesterone group ( n = 12) and estrogen-progesterone group ( n = 12). Three different dosages (5, 10 and 15 mg/ml) of progesterone were injected intraperitoneal (i.p.) separately and in combination with estrogen on 5 days, following which 24 h food and water intake and body weight were recorded for each injection. Results: It was observed that ovariectomy significantly increases food intake, water intake and body weight. I.p. injection of progesterone resulted in a dose-dependent increase in water intake without significant alteration in food intake and body weight. Anorectic effect of estrogen and dipsogenic effect of progesterone were prominent when estrogen and progesterone were injected combinely. Conclusion: It was concluded that estrogen inhibits food and water intake and progesterone facilitates water intake without affecting body weight. The effects of estrogen and progesterone are independent of each other.

Regulative Roles of Ghrelin in Ingestive Behavior, Upper Gastrointestinal Motility, and Secretion

Ghrelin was recently identified as the first endogenous ligand for growth hormone secretagogue receptors (previously known as orphan receptors). Two major molecular forms of ghrelin are found in the stomach and plasma: acyl ghrelin with O-n-octanoylated serine at position 3 and des-acyl ghrelin. Interestingly, these distinct molecular forms play contrasting roles in ingestive behavior, upper gastrointestinal motility, and gastric acid secretion. Acyl ghrelin stimulates food intake both in fed and fasted rodents and induces adiposity, alleviates ingestive behavior, stimulates gastrointestinal motor activity and gastric acid secretion, and accelerates gastric emptying in several species. In contrast, des-acyl ghrelin has been demonstrated to disrupt gastric motility in rats and delay gastric emptying in mice and rats. Thus, acyl ghrelin is a potent stimulator of ingestive behavior, gastrointestinal motility, and gastric acid secretion, whereas des-acyl ghrelin exerts opposing effects on ingestive behavior and gastrointestinal motility but does not affect gastric acid secretion. Ghrelin is expected to be used in various applications such as therapeutic strategies for obesity, anorexia, cachexia, and cardiovascular disease in the clinical setting. In this article, we review the evidence on the roles of acyl ghrelin and des-acyl ghrelin in the regulation of ingestive behavior, upper gastrointestinal motility, and gastric acid secretion in mammals; moreover, we mention the effects of ghrelin on oral functions.

Regulation of Ingestive Behaviors in the Rat by GSK1521498, a Novel μ-Opioid Receptor-Selective Inverse Agonist

μ-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with κ-opioid receptors (KOR) and δ-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with μ receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.

Microinjection of NMDA Receptor Agents into the Central Nucleus of the Amygdale Alters Water Intake in Rats

The central nucleus of the amygdala (CeA) is a forebrain structure which is important in regulation of ingestive behavior and there is direct and circumstantial evidence to indicate that some circuits involved with feeding behavior include glutamatergic elements. The present study examined whether administration of NMA (N-Methyl-DL-aspartic acid) or MK801 into the CeA altered water intake under deprivation. Materials and Methods Animals were deprived for 24 hr before tested for water intake. NMDA (N-methyl-D-aspartate) glutamatergic receptor agonist, NMA and its antagonist, MK801 were infused bilaterally, and water intake measured for 1 hr thereafter. Results The intra-CeA injection of NMDA glutamatergic agonist, NMA (0.25, 0.5 and 0.75 µg/rat) increased water intake (P<0.05). However, administration of NMDA glutamatergic antagonist, MK801 (0.25, 0.5 and 1 µg/rat) decreased water intake significantly (P<0.05). Conclusion These data suggest that NMDA receptors in the CeA are responsible for the glutamatergic modulation of water intake in this nucleus.

Nesfatin-1 increases anxiety- and fear-related behaviors in the rat

Nesfatin-1, derived from the protein NEFA/nucleobindin2 (NUCB2), is a newly identified peptide that acts as a potent satiety agent. It has been reported that peptides involved in the regulation of ingestive behavior are also involved in the regulation of the stress response. However, the relation between nesfatin-1 and stressor-related behaviors like anxiety and/or fear has not yet been investigated. The effects of intracerebroventricular (ICV) injection of nesfatin-1 (0, 5, and 25 pmol/3 microl) were assessed in several paradigms that are thought to reflect anxiety and/or fear in rats. Consistent with an anxiogenic effect, nesfatin-1 dose-dependently decreased the percentage of time spent on the open arms of the elevated plus maze, increased latency to approach, and decreased consumption of a palatable snack in an anxiogenic (unfamiliar) environment. Moreover, ICV nesfatin-1 increased the fear-potentiated startle response and the time spent freezing to both context and conditioned cues in a conditioned emotional response test. These findings suggest that in addition to its role as a satiety peptide, nesfatin-1 may also be involved in the mediation of anxiety- and/or fear-related responses.

Regulation of Ingestive Behavior, the Upper Gastrointestinal Motility and Gastric Acid Secretion by Ghrelin in Mammals

Ghrelin, a novel 28-amino acid peptide, was recently identified as the first endogenous ligand for growthhormone secretagogue receptors (previously known as orphan receptors), and discovered by “reverse pharmacology”. The ghrelin peptide features a unique post-translational modification of O-n-octanoylation at serine 3, and is secreted from X/A cells in gastric oxyntic glands into the blood circulation. Two major molecular forms of ghrelin are found in the stomach and plasma: acyl ghrelin with O-n-octanoylated serine in the position 3, and des-acyl ghrelin. Among dozens of enzymes, hormones and other factors secreted by the gastrointestinal tract in response to food in the lumen, acyl ghrelin is the only gastrointestinal signal to increase meal size. Acyl ghrelin stimulates food intake both in free-feeding (naturally fed) and food-deprived (fasted) rodents, and induces adiposity. Also, acyl ghrelin ameliorates cancer cachexia in nude mice, and alleviates ingestive behavior induced by cancer chemotherapy-related dyspepsia in normal rats. However, des-acyl ghrelin counteracts the metabolic but not the neuroendocrine response to acyl ghrelin. Transgenic mice overexpressing des-acyl ghrelin have been shown small phenotype. In addition, des-acyl ghrelin inhibits food intake in food-deprived mice and rats. Acyl ghrelin stimulates gastrointestinal motor activity and accelerates gastric emptying in rats, but not in dogs. On the contrary, des-acyl ghrelin has been shown to disrupt gastric motility in rats, and delay gastric emptying in mice and rats. For the majority of experiments, acyl ghrelin stimulates gastric acid secretion in rats, however, different results exist.

Gut-Brain Neuropeptides in the Regulation of Ingestive Behaviors and Obesity.

The prevalence of obesity has increased to epidemic proportions and has become an urgent public health problem. Obesity causes significant morbidity and mortality and its impact on health-care costs in the United States is growing dramatically. Apart from bariatric surgery treatment, options are limited. Future advances in treatment will rely on a better understanding of the pathogenesis and physiology of obesity. Alterations in gastrointestinal (GI) sensory-motor function and symptoms have been associated with obesity. GI neuroendocrine communications between the periphery and the brain regulate energy balance and ingestive behaviors. These interactions are largely mediated by the gut-brain peptides through negative and positive feedback loops that maintain energy homeostasis. Bariatric surgery has been shown effective, but the mechanisms of weight loss following these procedures clearly require further studies and a better understanding of the affects of bariatric surgery on the gut-brain neuropeptide homeostasis. Gut-brain peptides may provide attractive therapeutic targets in the fight against this very morbid disease. We review alterations in GI function and some of the more important gut-brain neuropeptides that occur in obesity.

Selective increase of dark phase water intake in neuropeptide-Y Y2 and Y4 receptor knockout mice

Neuropeptide-Y (NPY) is involved in the regulation of ingestive behaviour and energy homeostasis. Since deletion of the NPY Y2 and Y4 receptor gene increases and decreases food intake, respectively, we examined whether water intake during the light and dark phases is altered in Y2 and Y4 receptor knockout mice. The water consumption of mice staying in their home cages was measured by weighing the water bottles at the beginning and end of the light phase during 4 consecutive days. Control, Y2 and Y4 receptor knockout mice did not differ in their water intake during the light phase. However, during the dark phase Y2 and Y4 receptor knockout mice drank significantly more (46–63%, P < 0.05) water than the control mice. The total daily water intake over 24 h was also enhanced. The enhanced water intake during the dark phase was not altered by the β-adrenoceptor antagonist propranolol or the angiotensin AT1 receptor antagonist telmisartan (each injected intraperitoneally at 10 mg/kg). These data indicate that NPY acting via Y2 and Y4 receptors plays a distinctive role in the regulation of nocturnal water consumption. While β-adrenoceptors and angiotensin AT1 receptors do not seem to be involved, water intake in Y2 and Y4 receptor knockout mice may be enhanced because presynaptic autoinhibition of NPY release and inhibition of orexin neurons in the central nervous system are prevented.

Cannabinoids and the Regulation of Ingestive Behaviour

Over past centuries, Cannabis sativa (Delta(9)-tetrahydrocannabinol being the principal active ingredient) has been used extensively for both medicinal and recreational uses, and one widely reported effect is the onset of a ravenous appetite and eating behaviour. The pharmacological properties of such exogenous cannabinoids are mediated through the activation of two receptor subtypes, the CB(1) and CB(2) receptors. A number of endogenous ligands for these receptors, the endocannabinoids, have now also been identified allowing their effects on ingestive behaviour to be determined. In a number of species, including man, the administration of exogenous and endogenous cannabinoids leads to robust increases in food intake and can promote body weight gain. These effects are believed to be mediated through activation of the CB(1) receptor. Conversely, experiments with selective CB(1) receptor antagonists have demonstrated reductions in food intake and body weight with repeated compound administration. These reductions in body weight appear to be greater in obese animals and may be the result of a dual effect on both food intake and metabolic processes. Such findings have led to a number of pharmaceutical companies developing selective CB(1) receptor antagonists for the treatment of obesity. The most advanced compound is Sanofi-Synthelabo's inverse agonist, rimonabant (Acomplia; SR-141716), and early Phase III results have recently demonstrated significant reductions in body weight, waist circumference and improvement of lipid and glucose metabolism in overweight and obese humans. Accordingly, the cannabinoid system appears to have an important role in the regulation of ingestive behaviour in man and animals.

Body sodium and volume homeostasis.

maintenance of a “milieu interieur,” which allows our cells to function away from the ancient sea, is one of the most important functions of the body. Maintenance of constant extracellular osmolarity and sodium concentration depends on a precise balance between intake and excretion of sodium and

Possible contribution of brain angiotensin III to ingestive behaviors in baboons.

Recent experiments with specific aminopeptidase inhibitors in rats have strengthened earlier proposals that ANG III may be an important regulatory peptide in the brain. Central mechanisms regulating blood pressure, ingestive behaviors, and vasopressin release could be involved. Arguments in favor of a role for ANG III depend, in part, on the efficacy of ANG III as an agonist. These first studies in primates tested whether ANG III stimulates ingestive behaviors in baboons. Intracerebroventricular (ICV) infusions of ANG III were as potent as ANG II in stimulating water drinking and intake of NaCl solution. On the basis of this criterion and consistent with findings in rats, ANG III could be a main effector peptide in the regulation of ingestive behaviors in a primate.

The regulation of body weight: lessons from the seasonal animal.

The hypothalamus is a major regulatory centre involved in the control of many important physiological axes. One of these axes is the regulation of ingestive behaviour. Recent work using a combination of genetic-mutant mouse models together with targeted gene deletions has contributed much to our understanding of how neural pathways of the hypothalamus are involved in the regulation of energy balance in animals. These pathways are also relevant to human energy homeostasis. as mutations in key genes are correlated with obesity. Many of the genes identified mediate the effects of leptin, and are therefore primarily involved in sensing and responding to peripheral signals. In seasonal animals, such as the Siberian hamster (Phodopus sungorus), there is evidence for a higher level of regulation. The systems involved regulate body weight around an apparent 'set-point' through the action of photoperiod via the neurohormone, melatonin. The ability to manipulate energy balance through photoperiod (and melatonin) in the seasonal-animal model offers novel opportunities to identify further fundamental aspects of the control mechanisms involved in the central control of energy homeostasis and body weight.

Alterations in monoamines and GABA in the ventromedial and paraventricular nuclei of the hypothalamus following cold exposure: a reduction in noradrenaline induces hyperphagia

A microdialysis technique for the in vivo assessment of the monoaminergic and GABAergic levels in the ventromedial (VMN) and paraventricular nuclei (PVN) of the hypothalamus was used in order to examine the activities of neurons that project to the hypothalamic regions and are implicated in the regulation of ingestive behavior and energy balance. Cold exposure increased food intake, as well as the circulating levels of glucose, noradrenaline (NA), 3,5,3′-triiodothyronine, and corticosterone. The dialysate concentrations of NA, dopamine (DA), serotonin (5-HT), and γ-aminobutyric acid (GABA) in the VMN all decreased after exposure to cold. The changes in extracellular NA, DA, and GABA in the PVN under cold conditions were similar to those in the VMN. NA release in the VMN or PVN was decreased after local electrolytic lesions, which significantly increased food intake. Thus, low activities of noradrenergic axons of neurons terminating in the VMN and PVN may be a good mechanism to induce feeding behavior. Extracellular 5-HT in the PVN was significantly increased, along with a significant decrease in 5-hydroxyindoleacetic acid, in cold-exposed rats, suggesting that serotonergic fibers terminating in the PVM are more closely related to the increases in adrenocortical and thyroid hormone secretion than to food intake. The neuronal activities, indicating that a sympathetic tone is activated on stimulation of the VMN and/or PVN, may be changes in GABAergic and/or serotonergic neurons.

Feeding induced by GABA-sub(A ) receptor stimulation within the nucleus accumbens shell: Regional mapping and characterization of macronutrient and taste preference.

This study investigated the areas of the nucleus accumbens shell involved in the modulation of feeding behavior by GABAergic stimulation and characterized this response using macronutrient diets as well as saline, sucrose, and saccharin solutions. The GABA agonist muscimol induced a pronounced feeding response when infused in the medial nucleus accumbens shell but not in the ventral or lateral accumbens shell. In the macronutrient preference study, muscimol increased the intake of both high fat and high carbohydrate diets when presented separately. When both diets were available simultaneously, muscimol stimulated feeding of both diets to the same degree. Muscimol elicited a robust increase in the consumption of sucrose solution. However, no effect of muscimol was demonstrated for water, saline, or saccharin intake. These findings provide evidence for a selective role for GABA-sensitive neurons in the medial accumbens shell in the regulation of ingestive behavior and further suggest that GABA(A) receptors in this region do not modulate palatability, macronutrient selection, or rewarding properties of food.

Role of the taste system in ingestive behavior. Studies in NaCl and fatty acid transduction.

The transduction of tastants involves a variety of mechanisms both within and across stimulus classes. Taste stimuli have been shown to permeate and block ion channels, activate both ionotropic and metabotropic receptors and directly permeate the membrane of taste receptor cells. Though significant progress has been made in recent years in elucidating the mechanisms of taste transduction, there has been comparatively little emphasis placed upon investigating how the transduction process in taste receptor cells is modulated. Moreover, because of the general opinion that the sense of taste has little or no direct role in the regulation of ingestive behavior, there have been few studies aimed at directly assessing the link between the performance of the peripheral gustatory system and underlying nutritional preferences. Recent work in our laboratory in NaCl and fatty acid transduction supports the idea that the transduction of taste stimuli is a very dynamic process that both contributes to the control of ingestive behavior and is reflective of underlying nutrient preferences.

Association between the amygdala and nucleus of the solitary tract in μ-opioid induced feeding in the rat

The central nucleus of the amygdala (CNA) and the nucleus of the solitary tract (NTS) are important in the regulation of ingestive behavior. We evaluated whether opioid–opioid signaling between the CNA and rostral NTS (rNTS) affect feeding behavior. To test this, rats were doubly cannulated with one cannula placed in the rNTS and one cannula in the CNA, allowing for co-administration of an opioid agonist into one site and an opioid antagonist into the other. Tyr- D-Ala-Gly-(me) Phe-Gly-ol (DAMGO) (2 nmol) injected into the CNA (CNA DAMGO) increased feeding more than two-fold compared to the vehicle-injected rats. This increase in food intake was blocked when doses of 26.5 and 79 nmol of naltrexone (NTX) were injected into the rNTS. In the reverse situation, rNTS DAMGO increased food intake above control levels, and CNA NTX blocked DAMGO-induced feeding when administrated in doses of 26.5 and 79 nmol. This suggests that a bi-directional opioid–opioid signaling pathway exists between the CNA and the rNTS which influences feeding via μ-opioid receptors.