Rebound Hyperphagia Research Articles

Daily GDF15 treatment has sex-specific effects on body weight and food intake and does not enhance the effects of voluntary physical activity in mice.

Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that suppresses food intake and causes weight loss. GDF15 also reduces voluntary physical activity and, thus, it is not clear whether combining GDF15 with exercise will be beneficial or if reductions in food intake would be offset by decreases in physical activity. We investigated how GDF15 treatment combined with voluntary wheel running (VWR) would impact weight gain, food intake, adiposity and indices of metabolic health in mice. High-fat fed male and female mice underwent daily GDF15 treatments and were given access to voluntary running wheels, or not, for 11days. In both sexes, VWR prevented weight gain. In males, GDF15 reduced food intake, as well as attenuated weight gain and the accumulation of adipose tissue, with no additional effect of VWR. In female mice, GDF15 did not impact body weight gain or body composition. GDF15 acutely reduced food intake in female mice but this was followed by a period of rebound hyperphagia and consequently GDF15 did not reduce total food intake in female mice. GDF15 treatment reduced wheel running distance in both sexes. There were main effects of VWR to improve glucose tolerance in female but not male mice. These findings show that GDF15has sex-specific effects on food intake and consequently weight gain and adiposity. There is no added benefit of combining GDF15 and voluntary physical activity for weight loss. Adaptive responses to acute caloric restriction induced by GDF15might limit its effectiveness as a weight loss tool in females. KEY POINTS: GDF15 is a stress-induced signalling factor that reduces food intake and voluntary physical activity. It is not known whether combining GDF15 treatment with voluntary wheel running would impart beneficial combined effects in attenuating weight gain and the accumulation of adipose tissue. In the present study, we demonstrate that GDF15 reduces food intake and prevents weight gain in male but not female mice consuming a high-fat diet and also that combining GDF15 with voluntary wheel running (VWR) does not lead to a greater dampening of weight gain. In female mice, GDF15 acutely reduced food intake, but this was followed by a period of rebound hyperphagia resulting in no differences in total food intake. In both sexes, VWR was equivalent, or superior to GDF15 in preventing weight gain.

The vital role of arcuate nociceptin/orphanin FQ neurones in mounting an oestradiol-dependent adaptive response to negative energy balance via inhibition of nearby proopiomelanocortin neurones.

We tested the hypothesis that N/OFQ neurones in the arcuate nucleus (N/OFQARC ) inhibit proopiomelanocortin (POMCARC ) neurones in a diet- and hormone-dependent manner to promote a more extensive rebound hyperphagia upon re-feeding following an 18h fast. We utilized intact male or ovariectomized (OVX) female mice subjected to ad libitum-feeding or fasting conditions. N/OFQARC neurones under negative energy balance conditions displayed heightened sensitivity as evidenced by a decreased rheobase threshold, increased firing frequency, and increased burst duration and frequency compared to ad libitum-feeding conditions. Stimulation of N/OFQARC neurones more robustly inhibited POMCARC neurones under fasting conditions compared to ad libitum-feeding conditions. N/OFQARC inhibition of POMCARC neurones is hormone dependent as chemostimulation of N/OFQARC neurones from fasted males and OVX females produced a sizable outward current in POMCARC neurones. Oestradiol (E2 ) markedly attenuated the N/OFQ-induced POMCARC outward current. Additionally, N/OFQ tonically inhibits POMCARC neurones to a greater degree under fasting conditions than in ad libitum-feeding conditions as evidenced by the abrogation of N/OFQ-nociceptin opioid peptide (NOP) receptor signalling and inhibition of N/OFQ release via chemoinhibition of N/OFQARC neurones. Intra-arcuate nucleus application of N/OFQ further elevated the hyperphagic response and increased meal size during the 6 h re-feed period, and these effects were mimicked by chemostimulation of N/OFQARC neurones in vivo. E2 attenuated the robust N/OFQ-induced rebound hyperphagia seen in vehicle-treated OVX females. These data demonstrate that N/OFQARC neurones play a vital role in mitigating the impact of negative energy balance by inhibiting the excitability of anorexigenic neural substrates, an effect that is diminished by E2 in females. KEY POINTS: Nociceptin/orphanin FQ (N/OFQ) promotes increased energy intake and decreased energy expenditure under conditions of positive energy balance in a sex- and hormone-dependent manner. Here it is shown that under conditions of negative energy balance, i.e. fasting, N/OFQ inhibits anorexigenic proopiomelanocortin (POMC) neurones to a greater degree compared to homeostatic conditions due to fasting-induced hyperexcitability of N/OFQ neurones. Additionally, N/OFQ promotes a sustained increase in rebound hyperphagia and increase in meal size during the re-feed period following a fast. These results promote greater understanding of how energy balance influences the anorexigenic circuitry of the hypothalamus, and aid in understanding the neurophysiological pathways implicated in eating disorders promoting cachexia.

Fasting inhibits excitatory synaptic input on paraventricular oxytocin neurons via neuropeptide Y and Y1 receptor, inducing rebound hyperphagia, and weight gain

Fasting with varying intensities is used to treat obesity-related diseases. Re-feeding after fasting exhibits hyperphagia and often rebound weight gain. However, the mechanisms underlying the hyperphagia and rebound remain elusive. Here we show that 24 h food restriction (24 h FR) and milder 50% FR, both depress synaptic transmission in the hypothalamic paraventricular nucleus (PVN) and induce acute hyperphagia in rats. 24 h FR is followed by weight rebound but 50% FR is not. Orexigenic neuropeptide Y (NPY) via the Y1 receptor (Y1R) inhibited the miniature excitatory postsynaptic current (mEPSC) on anorexigenic oxytocin neurons in the PVN. 24 h FR and 50% FR activated this neuronal pathway to induce acute hyperphagia on Days 1-3 and Days 1-2 after FR, respectively. 24 h FR induced large mEPSC depression, recurrent hyperphagia on Days 9-12 and rebound weight gain on Days 12-17, whereas 50% FR induced moderate mEPSC depression and sustained weight reduction. Transverse data analysis on Day 1 after 24 h FR and 50% FR demonstrated saturation kinetics for the mEPSC depression-hyperphagiacurve, implying hysteresis. The results reveal FR-driven synaptic plasticity in the NPY-Y1R-oxytocin neurocircuit that drives acute hyperphagia. FR with the intensity that regulates the synapse-feeding relay without hysteresis is the key for successful dieting.

1356-P: Investigating the Metabolic Function of an Orphan G Protein–Coupled Receptor in the Intestinal Epithelium

G protein-coupled receptors (GPCRs) in the gastrointestinal tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary nutrients as well as microbial metabolites. We recently identified that an orphan GPCR, Gpr17, was co-expressed in glucagon-like peptide-1 (GLP-1) -expressing EECs in human and rodent intestinal epithelium. However, it is unknown how Gpr17 ablation in the intestinal epithelium affects feeding behavior and satiety regulation. To address this question, we used genetic knockout approach to generate intestinal Gpr17-deficient mice and analyzed their glucose metabolism and feeding behavior. We showed that intestinal Gpr17-deficient mice had similar growth curve, body composition, and ad libitum food intake compared with littermate controls. We found that acute genetic ablation of Gpr17 in intestinal epithelium (iKO) improved oral glucose tolerance and glucose-stimulated insulin secretion (GSIS) in female and male mice. iKO mice responded to glucose or lipid ingestion with increased secretion of GLP-1, but not the other incretin glucose-dependent insulinotropic polypeptide (GIP) . Intestinal Gpr17-deficient mice responded to fasting-refeeding challenge with reduced fasting locomotor activity and less food intake after refeeding, suggesting increased satiety during the phase of rebound hyperphagia. Furthermore, comprehensive studies including gut morphology, gut epithelium heterogeneity by scRNA-seq, and microbiome analysis were examined but none of them was changed because of intestinal Gpr17 ablation. In addition, male Gpr17 whole body knockout mice have improved intraperitoneal glucose tolerance, and increased insulin sensitivity in hyperinsulinemic-euglycemic clamp studies. In conclusion, our work showed that ablation of intestinal Gpr17 signaling led to improved neurohormonal regulation to maintain metabolic homeostasis. Disclosure H.Ren: None. Funding National Institute of Health (R01DK120772)

Mice Deficient for an Intestinal G Protein-Coupled Receptor Expression Have Increased Satiety During Rebound Hyperphagia

Gut-derived hormones have been successfully developed as the therapeutic targets to combat the increasing prevalence of diabetes and obesity. G protein-coupled receptors (GPCRs) in the gastrointestinal (GI) tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary nutrients as well as microbial metabolites. We identified that an orphan GPCR, Gpr17, was expressed in the intestinal epithelium and found that loss of intestinal Gpr17 expression increased gut incretin hormone secretion from enteroendocrine cells (EECs). However, it is unknown how Gpr17 ablation in the intestinal epithelium affects feeding behavior and satiety regulation. To address this question, we used genetic knockout approach to generate intestinal Gpr17-deficient mice and analyzed their feeding behavior. Here we show that intestinal Gpr17-deficient mice had similar growth curve, body composition, and ad libitum food intake compared with littermate controls. Interestingly, intestinal Gpr17-deficient mice responded to fasting-refeeding challenge with reduced fasting locomotor activity and less food intake after refeeding, suggesting increased satiety during the phase of rebound hyperphagia. Moreover, we performed fasting-refeeding challenge with Gpr17-deficient mice fed on high-fat diet (HFD), and our meal pattern analysis revealed that these mice had reduced meal duration of the first meal after refeeding. In conclusion, our genetic knockout studies in rodents showed that ablating intestinal Gpr17 increased satiety during rebound hyperphagia in the fasting-refeeding experimental paradigm. Intestinal Gpr17 could be developed as a therapeutic target to treat obesity by improving energy balance through gut hormone secretion and meal pattern control.

1895-P: Knocking Out Intestinal GPR17 Improves Glucose Homeostasis and Increases Satiety during Fasting-Refeeding Challenge

Aims: G protein-coupled receptors (GPCRs) in the intestinal enteroendocrine cells (EECs) regulate gut hormone secretion by responding to nutritional, microbial, and inflammatory factors, which contributes to the maintenance of glucose and energy homeostasis. We investigated the expression of GPR17, an orphan GPCR, in human and murine gastrointestinal tract and determined its metabolic roles using intestinal specific Gpr17 knockout mice. Methods: Gpr17 expression was profiled by quantitative RT-PCR, immunohistochemistry and flow cytometry. To elucidate the metabolic function of intestinal Gpr17, we generated constitutive (Vil1Cre,Gpr17-/-) and inducible (Vil1Cre-ERT2,Gpr17-/-) intestine-specific Gpr17 knockout mice and analyzed their metabolic features, including glucose tolerance, indirection calorimetry, feeding and microbiome composition. We measured nutrient-stimulated incretin secretion in Gpr17 knockout mice and cultured intestinal organoids. Results: We found that Gpr17 was enriched in Glucagon-like peptide 1 (GLP-1) expressing EECs in human and rodent intestine. Both constitutive and inducible Gpr17 intestinal knockout mice displayed improved glucose tolerance without alterations in pancreatic function and microbiota. In addition, Gpr17 intestinal knockout mice exhibited reduced foraging activity and less rebound hyperphagia in a fasting-refeeding paradigm. Notably, Gpr17 deficient mice and intestinal organoids responded to nutritional cues with enhanced GLP-1, but not GIP, secretion. Forskolin induced cAMP production was significantly inhibited by a synthetic Gpr17 agonist in GLUTag cells overexpressing Gpr17. Conclusions: Our work suggests GPR17 signaling in the enteroendocrine cells fine-tunes GLP-1 secretion. Targeting intestinal GPR17 for appetite and glucose metabolism represents a potential therapeutic strategy for type 2 diabetes and obesity. Disclosure S. Yan: None. A. Reilly: None. J.M. Conley: None. H. Ren: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120772, R00DK098294); Indiana Diabetes Center (P30DK097512); Indiana Clinical and Translational Sciences Institute (UL1TR002529)

Inhibition of Adipose Tissue Angiogenesis Prevents Rebound Weight Regain after Calorie Restriction Independent of Hypothalamic Melanocortin System in Obese Mice Fed a High-Fat Diet

Prevention of rebound weight gain after dieting is essential to treat obesity. However, its attempts have been unsuccessful and the underlying mechanism remains unclear. In this study, we sought to investigate the role of adipose tissue (AT) vasculature in rebound weight gain after calorie restriction in obese mice fed a high-fat diet (HFD). Obese mice were randomly assigned to 4 groups including mice fed HFD ad libitum (CON), mice under 40% calorie restriction for 5 weeks (CR), 3 days of HFD ad libitum after CR (CRAL), or CRAL treated with TNP-470, an angiogenesis inhibitor (TNP). We compared parameters of energy balance, AT morphometry and remodeling, and hypothalamic neuropeptides gene expression among the groups. Rebound weight gain and food intake were significantly lower and the level of brown AT UCP-1 gene expression was higher in TNP group than CRAL group. Fat mass was significantly lower in TNP group than CRAL group and it was similar to CR group while lean mass was not different between TNP and CRAL groups. Notably, the CD31-positive area was not different in AT between CON, CR, and CRAL groups, indicating that AT vasculature was maintained independently of nutritional status. However, that tended to be lower in AT of TNP group compared to other groups, implicating that inhibition of AT vasculature might be crucial to suppress rebound weight gain after calorie restriction. Consistently, circulating leptin levels were significantly lower in TNP group than CRAL group. However, the pattern of hypothalamic neuropeptides gene expression was different from the changes in food intake among the groups, suggesting an existence of novel regulatory signals independent of melanocortin system. Taken together, these results suggested a critical role of AT vasculature in regulating rebound weight gain and hyperphagia after calorie restriction independent of hypothalamic melanocortin system. Disclosure H. Lee: None. M. Song: None. N. Ha: None. B. Jin: None. S. Choi: None. D. Kim: None.

Idalopirdine, a selective 5-HT6 receptor antagonist, reduces food intake and body weight in a model of excessive eating

Obesity, from early childhood onwards, is a common societal problem. The overconsumption of sweet, salty and high-fat products are the main factors that cause excessive weight gain. It is therefore necessary to search for new drugs that affect satiety centers and reduce the sense of hunger and caloric intake. It has been suggested that the blockade of 5-HT6 receptors may reduce food intake, and since idalopirdine is a clinically tested, selective 5HT6 receptor antagonist, it was chosen to be examined in animal models of obesity. The activity of idalopirdine was measured in the rat model of excessive eating. Animals were on a high caloric diet that consisted of milk chocolate with nuts, cheese, salted peanuts and condensed milk. During a four-week experiment, the rats had constant access to standard feed and water ad libitum. Idalopirdine was administered intraperitoneally at a dose 5 mg/kg b.w./day. To establish whether idalopirdine would effectively suppress the rebound hyperphagia that accompanies refeeding, it was administered after a 20 h food deprivation period. Pica behavior was evaluated after the administration of idalopirdine to confirm that the suppression of food intake was not caused by visceral illness. The effect of the four-week treatment with idalopirdine on the amount of peritoneal adipose tissue, and on lipid and carbohydrate profiles in rats was also examined. The statistical significance was calculated using the one-way ANOVA post-hoc Tukey Multiple Comparison Test or the two-way ANOVA post-hoc Bonferroni Multiple Comparison Test. Idalopirdine significantly reduced caloric intake and prevented the development of obesity in tested animals. Rats, that received idalopirdine, had a smaller amount of adipose tissue in the peritoneum as well as lower glucose, triglyceride and cholesterol levels in comparison to the control group. Moreover, an anorectic action was not caused by abnormalities of the gastrointestinal tract, such as nausea. The obtained results indicate that idalopirdine reduces caloric intake and could be considered for further tests as a potential treatment of obesity.

The role of ghrelin-responsive mediobasal hypothalamic neurons in mediating feeding responses to fasting

ObjectiveGhrelin is a stomach-derived hormone that affects food intake and regulates blood glucose. The best-characterized actions of ghrelin are mediated by its binding to and activation of the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Adequate examination of the identity, function, and relevance of specific subsets of GHSR-expressing neurons has been hampered by the absence of a suitable Cre recombinase (Cre)-expressing mouse line with which to manipulate gene expression in a targeted fashion within GHSR-expressing neurons. The present study aims to characterize the functional significance and neurocircuitry of GHSR-expressing neurons in the mediobasal hypothalamus (MBH), as they relate to ghrelin-induced food intake and fasting-associated rebound hyperphagia, using a novel mouse line in which Cre expression is controlled by the Ghsr promoter. MethodsA Ghsr-IRES-Cre mouse line that expresses Cre directed by the Ghsr promoter was generated. The line was validated by comparing Cre activity in reporter mice to the known brain distribution pattern of GHSR. Next, the requirement of MBH GHSR-expressing neuronal activity in mediating food intake in response to administered ghrelin and in response to fasting was assessed after stereotaxic delivery of inhibitory designer receptor exclusively activated by designer drugs (DREADD) virus to the MBH. In a separate cohort of Ghsr-IRES-Cre mice, stereotaxic delivery of stimulatory DREADD virus to the MBH was performed to assess the sufficiency of MBH GHSR-expressing neuronal activity on food intake. Finally, the distribution of MBH GHSR-expressing neuronal axonal projections was assessed in the DREADD virus-injected animals. ResultsThe pattern of Cre activity in the Ghsr-IRES-Cre mouse line mostly faithfully reproduced the known GHSR expression pattern. DREADD-assisted inhibition of MBH GHSR neuronal activity robustly suppressed the normal orexigenic response to ghrelin and fasting-associated rebound food intake. DREADD-assisted stimulation of MBH GHSR neuronal activity was sufficient to induce food intake. Axonal projections of GHSR-expressing MBH neurons were observed in a subset of hypothalamic and extra-hypothalamic regions. ConclusionsThese results suggest that 1) activation of GHSR-expressing neurons in the MBH is required for the normal feeding responses following both peripheral administration of ghrelin and fasting, 2) activation of MBH GHSR-expressing neurons is sufficient to induce feeding, and 3) axonal projections to a subset of hypothalamic and/or extra-hypothalamic regions likely mediate these responses. The Ghsr-IRES-Cre line should serve as a valuable tool to further our understanding of the functional significance of ghrelin-responsive/GHSR-expressing neurons and the neuronal circuitry within which they act.

The first of the viscoceuticals? A shear thickening gum induces gastric satiety in rats.

We examined the effect of gavage of 4 ml of a viscous shear-thickening polysaccharide solution (15% w/w) extracted from the fronds of the mamaku tree fern (Cythea medullaris) in reducing appetite and delaying gastric emptying in twenty six Sprague Dawley rats. After two weeks habituation to a pelleted chow, the rats were gavaged on alternate days with either the mamaku extract or with the same volume of deionised water for a total of five times over a period of two weeks. The body mass and food intake of each rat were determined daily and the weights of their stomach contents determined on euthanasia two hours after the final gavage. The rats gavaged with the mamaku gum consumed significantly lower quantities of chow on the day of gavage. The weights of the stomach contents of rats two hours after gavage with mamaku extract were significantly greater than those following gavage with water. The failure of the rats dosed with mamaku to lose body weight likely resulted from the overall adverse effect of gavage on food intake, the limited numbers of doses of the gum and the rebound hyperphagia on days when the rats were not gavaged. Together the results indicate that gavage with mamaku gum delayed gastric emptying with respect to that of rats dosed with water and supressed appetite for 12-24 hours after dosage.

Can early protein restriction induce the development of binge eating?

We tested the hypothesis that perinatal undernourishment is a factor for binge eating. At 52 days rats born from dams fed on 17% protein (Control) or 8% protein (Undernourished) were distributed into four groups, two of which continued to be fed ad libitum chow and two were submitted to three consecutive Restricted/Refeeding (R/R) cycles. According to the following schedule: Control Naïve (from mothers fed 17% protein/no restriction phase); Control Restricted (from mothers fed 17% protein/restriction phase); Undernourished Naïve (from mothers fed 8% protein/no restriction phase); and Undernourished Restricted (from mothers fed 8% protein/restriction phase). Each cycle consisted of a restriction phase (in the first four days 40% of the mean daily individual chow intake was offered for consumption), followed by a refeeding phase (4 days of chow ad libitum). After the three cycles, all animals were subjected to a feeding test (chow diet and palatable food ad libitum for 24h). During the feeding test, the Undernourished Restricted demonstrated rebound hyperphagia during 2, 4 and 6h. These results suggest the perinatal undernourishment cannot contribute to a binge eating phenotype.

Single rapamycin administration induces prolonged downward shift in defended body weight in rats.

Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.

Changes in NPY and POMC, but not serotonin transporter, following a restricted feeding/repletion protocol in rats

Serotonin (5-HT) plays a key role in controlling food intake and feeding behaviour and drugs targeting the 5-HT transporter (SERT) at the synaptic cleft have been used to treat feeding related disorders. To test the hypothesis that SERT might be one of the etiologic factors in the rebound hyperphagia that frequently follows the abandoning of calorie restriction diets, brain SERT content and gene expression were assessed in a restricted feeding/repletion (RFR) protocol in female rats. Animals were food-restricted (2 h access to food per day) for 7 consecutive days and then allowed constant free access to food (FAF). This intermittent fasting protocol resulted in rebound hyperphagia. Higher levels of plasma corticosterone during fasting in food-deprived rats were used as an index of hypothalamic-pituitary-adrenal axis activation. Neither brain SERT density nor expression was modified following the RFR protocol. Nevertheless, with respect to other messengers involved in eating behaviour, in the presence of low plasma leptin levels, an increase in NPY expression and a parallel decrease in POMC expression were observed in the hypothalamic arcuate nucleus of rats killed just before rebound hyperphagia. Food-restricted animals provide a tool for the further study of neurochemical alterations and for the development of new drugs to treat alterations that may occur in humans when dieting is abandoned.

Acute and chronic effects of β-hydroxybutyrate on food intake and body weight.

The use of low carbohydrate diets to control body weight has increased in recent years. In humans, one consequence of such a diet is the production of ketone bodies, which are used by the brain and body as fuel when glucose is in short supply. It has been previously demonstrated that chronic intracerebroventricular (ICV) administration of β -hydroxybutyrate ( β -HB), one of three ketone bodies, reduces body weight and food intake in rats over a 28 day period. The mechanisms by which β -HB reduces food intake and the effects of acute administration of this ketone body are currently unknown. The present series of experiments examined the effects of acute β -HB administration (intraperitoneally, IP) and long-term (chronic ICV infusion) β -HB treatment on food intake, body weight, and endocrine profiles. Acute β -HB (100 and 200 μmol) produced a significant, yet transient, decrease in food intake, as compared to saline-treated controls (1.34 and 1.36 vs. 3.43 g, respectively ( p <0.05 in each case)). This decrease was followed by rebound hyperphagia: food intake was significantly increased 24 h after injection (100 μmol), as compared to controls. Chronic ICV infusion of β -HB (60 μmol/hr over 28 days) administered via osmotic minipump and delivered into the lateral ventricle produced a significant decrease food intake. In addition, β -HB-treated animals tended to have a lower rate of body weight gain and decreased plasma insulin levels. Collectively, these data suggest acute and chronic effects of β -HB on food intake and body weight, the mechanisms of which are currently under investigation.

A Role for Brain-Specific Homeobox Factor Bsx in the Control of Hyperphagia and Locomotory Behavior

Food intake and activity-induced thermogenesis are important components of energy balance regulation. The molecular mechanism underlying the coordination of food intake with locomotory behavior to maintain energy homeostasis is unclear. We report that the brain-specific homeobox transcription factor Bsx is required for locomotory behavior, hyperphagia, and expression of the hypothalamic neuropeptides Npy and Agrp, which regulate feeding behavior and body weight. Mice lacking Bsx exhibit reduced locomotor activity and lower expression of Npy and Agrp. They also exhibit attenuated physiological responses to fasting, including reduced increase of Npy/Agrp expression, lack of food-seeking behavior, and reduced rebound hyperphagia. Furthermore, Bsx gene disruption rescues the obese phenotype of leptin-deficient ob/ob mice by reducing their hyperphagia without increasing their locomotor activity. Thus, Bsx represents an essential factor for NPY/AgRP neuronal function and locomotory behavior in the control of energy balance.

Altered Hypothalamic Signaling and Responses to Food Deprivation in Rats Fed a Low‐Carbohydrate Diet

To model how consuming a low-carbohydrate (LC) diet influences food intake and body weight. Food intake and body weight were monitored in rats with access to chow (CH), LC-high-fat (HF), or HF diets. After 8 weeks, rats received intracerebroventricular injections of a melanocortin agonist (melanotan-II) and antagonist (SHU9119), and feeding responses were measured. At sacrifice, plasma hormones and hypothalamic expression of mRNA for proopiomelanocortin (POMC), melanocortin-4 receptor, neuropeptide Y (NPY), and agouti related protein (AgRP) were assessed. A second set of rats had access to diet (chow or LC-HF) for 4 weeks followed by 24 h food deprivation on two occasions, after which food intake and hypothalamic POMC, NPY, and AgRP mRNA expression were measured. HF rats consumed more food and gained more weight than rats on CH or LC-HF diets. Despite similar intakes and weight gains, LC-HF rats had increased adiposity relative to CH rats. LC-HF rats were more sensitive to melanotan-II and less sensitive to SHU9119. LC-HF rats had increased plasma leptin and ghrelin levels and decreased insulin levels, and patterns of NPY and POMC mRNA expression were consistent with those of food-deprived rats. LC-HF rats did not show rebound hyperphagia after food deprivation, and levels NPY, POMC, and AgRP mRNA expression were not affected by deprivation. Our results demonstrate that an LC diet influences multiple systems involved in the controls of food intake and body weight. These data also suggest that maintenance on an LC-HF diet affects food intake by reducing compensatory responses to food deprivation.

A comparative proteomic analysis of the rat brain during rebound hyperphagia induced by space-restriction

Although neurochemical changes have been reported in the brain in animal models of binge eating, biochemical changes of specific proteins in the brain are unknown. Our aim was to elucidate brain proteins altered in rats during enhanced rebound hyperphargia. Rats were deprived of food for 22 h/day for 6 days, then allowed free access to food for 24 h in normal cages (rebound hyperphargia) or in space-restricted cages (enhanced rebound hyperphargia). Proteins extracted from the rat brain were separated by two-dimensional gel electrophoresis, and compared with those from control rats freely fed for 7 days in normal cages. Proteins expressed differently from controls were identified by N-terminal amino acid sequencing and mass fingerprinting using a MALDI-TOF mass spectrometer. Among proteins in the corpus striatum, frontal lobe, hippocampus and thalamus/hypothalamus, ubiquitin C-terminal hydrolase L1 and peroxiredoxin 2 decreased in the hippocampus and phosphatidylethanolamine-binding protein increased in the thalamus/hypothalamus of rats with the enhanced rebound hyperphargia induced by space-restriction. In this study, we first demonstrated that three brain proteins changed in rats during enhanced rebound hyperphagia. These proteins might have pathophysiologic relevance to binge eating.

Adolescent Drug Addiction Treatment and Weight Gain

SUMMARY Neurotransmitter release in the nucleus accumbens use has been linked to self-administration and learning following drug use. This endogenous reward system is also activated following food intake or sex. Therefore, rebound hyperphagia following abstinence may be a mechanism to replenish the release of neurotransmitters in this reward system, leading to increased weight gain and a rise in Body Mass Index during recovery from substance abuse. In this report, we examined the relationship between supervised drug abstinence and increased weight gain among adolescents at a residential substance abuse treatment center. Mean weight change over time was followed by repeated analysis of weight and body mass index. Significant weight gain and body mass index increase was observed during supervised and confirmed abstinence from drug use. Furthermore, significant interactions between tobacco use and primary substance use disorder with weight gain was demonstrated by multivariate analysis of variance.

Preferential effects of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight gain of obese (fa/fa) compared to lean Zucker rats

The selective CB(1) receptor antagonist, SR 141716, has been demonstrated to reduce food consumption in a range of animal species. To assess the effect of chronic administration of SR 141716 on body weight and ingestive behaviour of lean and obese (fa/fa) Zucker rats. Lean and obese Zucker rats were orally dosed with SR 141716 (3, 10, 30 mg/kg PO), sibutramine (5 mg/kg PO) or vehicle for one week. Pair-fed controls provided insight as to whether the effect of SR 141716 on body weight was attributable to drug-induced hypophagia. Subsequently, the effect of chronic oral administration of SR 141716 (1, 3, 10 mg/kg) was assessed for 28 days. At the end of this period, all animals were given vehicle for 14 days. The incidence of wet-dog shakes, yawning, scratching, and grooming behaviours, was assessed after acute administration and at weekly intervals thereafter for 4 weeks. SR 141716 dose-dependently decreased food intake and body weight gain in both lean and obese animals. The inhibition of food intake and body weight gain was greater in obese Zuckers than in lean Zucker controls. Changes in the body weights of pair-fed controls closely paralleled those of their drug-treated counterparts. Chronic 28-day treatment led to a maintained reduction of body weight gain. Withdrawal of SR 141716 on day 28 resulted in rebound hyperphagia and a significant weight gain. On acute administration, SR 141716 dose-dependently induced motor behaviours that showed tolerance upon repeated administration. These data indicate that chronic oral treatment with SR 141716 significantly reduces the food intake and body weight gain of obese and lean Zucker rats, an effect that is greater in obese animals and reversible upon drug withdrawal.

Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice.

C75 is a potent inhibitor of fatty acid synthase that acts centrally to reduce food intake and body weight in mice; a single dose causes a rapid (>90%) decrease of food intake. These effects are associated with inhibition of fasting-induced up-regulation and down-regulation, respectively, of the expression of orexigenic (NPY and AgRP) and anorexigenic (POMC and CART) neuropeptide messages in the hypothalamus. Repeated administration of C75 at a submaximal level, however, differentially affected food intake of lean and obese mice. With lean mice, C75 suppressed food intake by approximately 50% and, with obese mice (ob/ob and dietary-induced obesity), by 85-95% during the first day of treatment. Lean mice, however, became tolerant/resistant to C75 over the next 2-5 days of treatment, with food intake returning to near normal and rebound hyperphagia occurring on cessation of treatment. In contrast, ob/ob obese mice responded to C75 with a >90% suppression of food intake throughout the same period with incipient tolerance becoming evident only after substantial weight loss had occurred. Dietary-induced obese mice exhibited intermediate behavior. In all cases, a substantial loss of body weight resulted. Pair-fed controls lost 24-50% less body weight than C75-treated mice, indicating that, in addition to suppressing food intake, C75 may increase energy expenditure. The decrease in body weight by ob/ob mice was due primarily to loss of body fat. In contrast to the short-term effects of C75 on "fasting-induced" changes of hypothalamic orexigenic and anorexigenic neuropeptide mRNAs, repeated administration of C75 either had the inverse or no effect as tolerance developed.