Decreased Meal Size Research Articles

The influence of estrogen response element ERα signaling in the control of feeding behaviors in male and female mice

Circulating 17β-estradiol (E2) controls energy homeostasis and feeding behaviors primarily by its nuclear receptor, estrogen receptor (ER) α. As such, it is important to understand the role of ERα signaling in the neuroendocrine control of feeding. Our previous data indicated that the loss of ERα signaling through estrogen response elements (ERE) alters food intake in a female mouse model. Hence, we hypothesize that ERE-dependent ERα is necessary for typical feeding behaviors in mice. To test this hypothesis, we examined feeding behaviors on low-fat diet (LFD) and high-fat diet (HFD) in three mouse strains: total ERα knockout (KO), ERα knockin/knockout (KIKO), which lack a functional DNA-binding domain, and their wild type (WT) C57 littermates comparing intact males and females and ovariectomized females with or without E2 replacement. All feeding behaviors were recorded using the Biological Data Acquisition monitoring system (Research Diets). In intact male mice, KO and KIKO consumed less than WT mice on LFD and HFD, while in intact female mice, KIKO consumed less than WT and KO. These differences were primarily driven by shorter meal duration in the KO and KIKO. In ovariectomized females, E2-treated WT and KIKO consumed more LFD than KO driven in part by an increase in meal frequency and a decrease in meal size. On HFD, WT consumed more than KO with E2, again due to effects on meal size and frequency. Collectively, these suggest that both ERE-dependent and -independent ERα signaling are involved in feeding behaviors in female mice depending on the diet consumed.

151-OR: 27-Hydroxycholesterol Inhibits Food Intake through ERa-Mediated Activation of POMC Neurons

Oxysterols are metabolites of cholesterol produced in peripheral tissues as a means to eliminate cholesterol. 27-hydroxycholesterol (27HC) is the most abundant oxysterols and can cross the blood-brain barrier. Interestingly, 27HC has recently been identified as an endogenous selective estrogen receptor modulator (SERM) for both estrogen receptor α and β (ERα/β) . Considering the regulatory effects of brain estrogen/ERα signaling on energy metabolism, we hypothesize that the endogenous SERM 27HC binds with ERα in the arcuate nucleus of hypothalamus (ARH) of brain to modulate energy homeostasis.In supporting this point of view, we found that a single acute intracerebroventricular (ICV) injection of 27HC inhibited food intake in both male and female mice. The reduced food intake was attributed to decreased meal size and increased intermeal intervals. This anorexigenic effect was also associated with the increased c-fos expression in the pro-opiomelanocortin neurons in ARH (POMCARH) . Using brain slice patch-clamp recording, we consistently showed that 27HC dose-dependently actives POMCARH in an ERα-dependent manner, suggesting a mediating role of ERα expressed by POMCARH neurons. Notably, we further revealed that the inhibitory effects of 27HC on food intake were blocked by antagonists for ERα or POMC downstream melanocortin 3/4 receptors. In addition, chemogenetic inhibition of POMCARH neurons also blunted the anorexigenic effects of 27HC in mice. Collectively, these results support a model that 27HC acutely inhibits food intake by acting on ERα to stimulate POMCARH neuronal activity. This 27HC/ERα/POMC signaling pathway may serve as a critical defending mechanism against high-fat diet-induced obesity. Disclosure H. Ye: None. B. Feng: None. D. Dixit: None. Y. He: None. P. Xu: None.

1313-P: Short-Chain Fatty Acids Decrease Food Intake through Free Fatty Acid Receptors in the Brain

The influence of gut bacteria on host energy homeostasis is increasingly recognized, but mechanistic links are lacking. The gut microbiota digests and ferments nutrients, which result in short-chain fatty acids (SCFAs) . The body senses these nutrients in large part through free fatty acid receptors 2 (FFA2) and 3 (FFA3) . Accumulating evidence indicates that the gut microbiota/SCFAs interact with the central nervous system (CNS) to regulate brain metabolic function. Consistently, we found that a single acute intracerebroventricular (ICV) injection of acetate (ACE) , propionate (PRO) , or butyrate (BUT) dose-dependently inhibited food intake in an FFA2/3-dependent manner. The reduced food intake induced by ACE, PRO, or BUT was attributed to decreased meal size or increased intermeal interval. These regulatory effects on meal patterns were blunted in FFA2 and FFA3 double-receptor knockout mice, suggesting a mediating role of brain FFA2/3. Interestingly, RNAscope analysis showed that FFA3 but not FFA2 highly expressed in the cerebellar granule neurons. Using brain slice patch-clamp, we consistently showed that PRO or FFA3-selective agonists inhibited these granule neurons. Notably, the hyperpolarization effects of PRO on cerebellar granule neurons were blocked by pertussis toxin (PTX) , a G-protein coupled receptor subunit Gi/o blocker, further supporting an FFA3-Gi/o-mediated inhibition on granule neurons. These results suggest a model that SCFAs inhibit food intake through FFA3 expressed by the cerebellar granule neurons. Key words: SCFA; Brain; FFA3 Disclosure P. Luo: None. P. Xu: None. H. Ye: None. B.T. Layden: None. Y. He: None. V.C. Torres Irizarry: None.

Neuronal GHS-R Differentially Modulates Feeding Patterns under Normal and Obesogenic Conditions.

The orexigenic hormone ghrelin increases food intake and promotes obesity through its receptor, growth hormone secretagogue receptor (GHS-R). We previously reported two neuron-specific GHS-R knockout mouse lines, namely pan-neuronal deletion by Syn1-cre and hypothalamic deletion by AgRP-cre, exhibiting differential diet-dependent effects on body weight. GHS-R deficiency in neurons elicited less pronounced metabolic effects under regular diet (RD) than high fat diet (HFD). While there was no difference in total food intake of HFD in either mouse line, Syn1-cre; Ghsrf/f mice showed much greater anti-obesity effect than that of AgRP-cre; Ghsrf/f mice. Meal feeding pattern is known to have a major impact on energy homeostasis and obesity development. Here, we investigated the feeding behaviors of these two neuron-specific GHS-R knockout mice under RD and HFD feeding, by assessing meal number, meal size, meal duration, and feeding frequency. Under the normal diet, RD-fed Syn1-cre; Ghsrf/f mice showed a decreased meal size in dark phase, while RD-fed AgRP-cre; Ghsrf/f mice showed an increased meal duration in dark phase. Under the obesogenic diet, HFD-fed Syn1-cre; Ghsrf/f mice displayed reduced meal numbers in light phase and increased feeding in both light and dark phases, whereas HFD-fed AgRP-cre; Ghsrf/f mice showed a decreased meal duration in the light phase only. Consistently, the expression of neuropeptides (Neuropeptide Y and Orexin) was increased in the hypothalamus of RD-fed Syn1-cre; Ghsrf/f mice, whereas the expression of cannabinoid receptor type 1 (CB1) was increased in the hypothalamus of HFD fed Syn1-cre; Ghsrf/f mice. Overall, feeding pattern changes were more pronounced in Syn1-cre; Ghsrf/f mice than that in AgRP-cre; Ghsrf/f mice, and HFD elicited greater alteration than RD. While AgRP-cre; Ghsrf/f mice consumed HFD meals faster during the day (showing shorter meal duration), Syn1-cre; Ghsrf/f mice ate few HFD meals during the light phase and ate slowly throughout the day (showing longer meal duration in both phases). Our findings reveal that neuronal GHS-R regulates energy homeostasis by altering feeding patterns, and differentially modulates feeding patterns in a site- and diet-dependent manner. The distinctive data in these two mouse lines also suggest that eating slowly during the optimal feeding period (dark phase for mice) may be beneficial in combating obesity.

The gravitostat protects diet-induced obese rats against fat accumulation and weight gain.

The gravitostat is a novel homeostatic body weight-regulating mechanism, mostly studied in mice, and recently confirmed in obese humans. In the present study, we explored the effect of weight loading on metabolic outcomes, meal patterns and parameters linked to energy expenditure in both obese and lean rats. Diet-induced obese (DIO) and lean rats were implanted with capsules weighing either 15% of biological body weight (load) or empty capsules (1.3% of body weight; controls). Loading protected against fat accumulation more markedly in the DIO group. In line with this, the obesity-related impairment in insulin sensitivity was notably ameliorated in DIO rats upon loading, as revealed by the reduction in serum insulin levels and homeostatic model assessment for insulin resistance index scores. Although 24-hour caloric intake was reduced in both groups, this effect was greater in loaded DIO rats than in loaded lean peers. During days 10-16, after recovery from surgery, loading: (i) decreased meal size in both groups (only during the light phase in DIO rats) but this was compensated in lean rats by an increase in meal frequency; (ii) reduced dark phase locomotor activity only in lean rats; and (iii) reduced mean caloric efficiency in DIO rats. Muscle weight was unaffected by loading in either group. Dietary-obese rats are therefore more responsive than lean rats to loading.

Gastrointestinal Vagal Afferents and Food Intake: Relevance of Circadian Rhythms.

Gastrointestinal vagal afferents (VAs) play an important role in food intake regulation, providing the brain with information on the amount and nutrient composition of a meal. This is processed, eventually leading to meal termination. The response of gastric VAs, to food-related stimuli, is under circadian control and fluctuates depending on the time of day. These rhythms are highly correlated with meal size, with a nadir in VA sensitivity and increase in meal size during the dark phase and a peak in sensitivity and decrease in meal size during the light phase in mice. These rhythms are disrupted in diet-induced obesity and simulated shift work conditions and associated with disrupted food intake patterns. In diet-induced obesity the dampened responses during the light phase are not simply reversed by reverting back to a normal diet. However, time restricted feeding prevents loss of diurnal rhythms in VA signalling in high fat diet-fed mice and, therefore, provides a potential strategy to reset diurnal rhythms in VA signalling to a pre-obese phenotype. This review discusses the role of the circadian system in the regulation of gastrointestinal VA signals and the impact of factors, such as diet-induced obesity and shift work, on these rhythms.

Insulin signaling in AgRP neurons regulates meal size to limit glucose excursions and insulin resistance.

The importance of hypothalamic insulin signaling on feeding and glucose metabolism remains unclear. We report that insulin acts on AgRP neurons to acutely decrease meal size and thereby limit postprandial glucose and insulin excursions. The promotion of insulin signaling in AgRP neurons decreased meal size without altering total caloric intake, whereas the genetic ablation of the insulin receptor had the opposite effect. The promotion of insulin signaling also decreased the intake of sucrose-sweetened water or high-fat food over standard chow, without influencing food-seeking and hedonic behaviors. The ability of heightened insulin signaling to override the hedonistic consumption of highly palatable high-fat food attenuated the development of systemic insulin resistance, without affecting body weight. Our findings define an unprecedented mechanism by which insulin acutely influences glucose metabolism. Approaches that enhance insulin signaling in AgRP neurons may provide a means for altering feeding behavior in a nutrient-dense environment to combat the metabolic syndrome.

New roles for prokineticin 2 in feeding behavior, insulin resistance and type 2 diabetes: Studies in mice and humans

ObjectiveProkineticin 2 (PROK2) is a hypothalamic neuropeptide that plays a critical role in the rhythmicity of physiological functions and inhibits food intake. PROK2 is also expressed in the main olfactory bulb (MOB) as an essential factor for neuro-and morphogenesis. Since the MOB was shown to be strongly involved in eating behavior, we hypothesized that PROK2 could be a new target in the regulation of food intake and energy homeostasis, through its effects in the MOB. We also asked whether PROK2 could be associated with the pathophysiology of obesity, the metabolic syndrome (MetS), and type 2 diabetes (T2D) in humans. MethodsWe assessed in wild type mice whether the expression of Prok2 in the MOB is dependent on the nutritional status. We measured the effect of human recombinant PROK2 (rPROK2) acute injection in the MOB on food intake and olfactory behavior. Then, using a lentivirus expressing Prok2-shRNA, we studied the effects of Prok2 underexpression in the MOB on feeding behavior and glucose metabolism. Metabolic parameters and meal pattern were determined using calorimetric cages. In vivo 2-deoxyglucose uptake measurements were performed in mice after intraperitoneally insulin injection. Plasmatic PROK2 dosages and genetic associations studies were carried out respectively on 148 and more than 4000 participants from the D.E.S.I.R. (Data from an Epidemiologic Study on the Insulin Resistance Syndrome) cohort. ResultsOur findings showed that fasting in mice reduced Prok2 expression in the MOB. Acute injection of rPROK2 in the MOB significantly decreased food intake whereas Prok2-shRNA injection resulted in a higher dietary consumption characterized by increased feeding frequency and decreased meal size. Additionally, Prok2 underexpression in the MOB induced insulin resistance compared to scrambled shRNA-injected mice. In the human D.E.S.I.R. cohort, we found a significantly lower mean concentration of plasma PROK2 in people with T2D than in those with normoglycemia. Interestingly, this decrease was no longer significant when adjusted for Body Mass Index (BMI) or calorie intake, suggesting that the association between plasma PROK2 and diabetes is mediated, at least partly, by BMI and feeding behavior in humans. Moreover, common Single Nucleotide Polymorphisms (SNPs) in PROK2 gene were genotyped and associated with incident T2D or impaired fasting glycemia (IFG), MetS, and obesity. ConclusionsOur data highlight PROK2 as a new target in the MOB that links olfaction with eating behavior and energy homeostasis. In humans, plasma PROK2 is negatively correlated with T2D, BMI, and energy intake, and PROK2 genetic variants are associated with incident hyperglycemia (T2D/IFG), the MetS and obesity.

The hindbrain is a site of energy balance action for prolactin-releasing peptide: feeding and thermic effects from GPR10 stimulation of the nucleus tractus solitarius/area postrema.

Prolactin-releasing peptide (PrRP) is a neuropeptide that suppresses food intake and increases body temperature when delivered to the forebrain ventricularly or parenchymally. However, PrRP's receptor GPR10 is widely distributed throughout the brain with particularly high levels found in the dorsomedial hindbrain. Thus, we hypothesized that hindbrain-directed PrRP administration would affect energy balance and motivated feeding behavior. To address this hypothesis, a range of behavioral and physiologic variables were measured in Sprague-Dawley rats that received PrRP delivered to the fourth ventricle (4V) or the nucleus of the solitary tract (NTS) at the level of the area postrema (AP). 4V PrRP delivery decreased chow intake and body weight, in part, through decreasing meal size in ad libitum maintained rats tested at dark onset. PrRP inhibited feeding when delivered to the nucleus tractus solitarius (NTS), but not to more ventral hindbrain structures. In addition, 4V as well as direct NTS administration of PrRP increased core temperature. By contrast, 4V PrRP did not reduce ad libitum intake of highly palatable food or the motivation to work for or seek palatable foods. The dorsomedial hindbrain and NTS/AP, in particular, are sites of action in PrRP/GPR10-mediated control of chow intake, core temperature, and body weight.

Fuels derived from starch digestion have different effects on energy intake and metabolic responses of cows in the postpartum period

Absorbed fuels from the digestion of starch include propionic acid (PA) produced by ruminal fermentation and glucose (GLU) from intestinal digestion, which may be partially metabolized to lactic acid (LA) by intestinal tissues. Our objective was to evaluate the effects of these fuels on dry matter intake (DMI) and feeding behavior of cows in the postpartum period. We hypothesized that these fuels affect feed intake differently and that their effects are related to differences in their hepatic metabolism. Glucose was expected to have little effect on feed intake because little or no GLU is extracted from the blood by the liver. Whereas both LA and PA are anaplerotic and can stimulate oxidation of acetyl CoA in hepatocytes, hepatic extraction of PA is greater than LA, which depends on cytosolic redox state. Continuous isoenergetic infusions (150 kcal of ME/h) of PA, LA, or GLU or no infusion were administered abomasally to 8 ruminally cannulated multiparous Holstein cows (12.4 ± 6.2 d postpartum) in a duplicate 4 × 4 Latin square design experiment, with four 1-d infusion periods, balanced for carry-over effects. Treatment sequences were assigned to cows randomly, and treatments included control (CON, no infusion), PA (0.41 mol/h), LA (0.46 mol/h), and GLU (0.22 mol/h). Solutions containing treatments were infused at 500 mL/h for 22 h/d and provided ∼3.3 Mcal/d. Feeding behavior was recorded by a computerized data acquisition system. Gross energy digestibility of the diet was determined for each cow and used to calculate metabolizable energy intake (MEI) from the diet. Total MEI was calculated as the sum of MEI from the diet plus energy from infusions. Data were analyzed statistically with a mixed model including the fixed effect of treatment and random effects of block and cow within block. Each treatment was compared with CON by contrasts. Compared with CON, PA decreased DMI by 24% (14.3 vs. 18.9 kg/d) and total MEI by 13% (34.8 vs. 40.2 Mcal/d) with a tendency to decrease meal frequency. Lactic acid decreased DMI by 14% (16.3 vs. 18.9 kg/d) compared with CON by decreasing meal size 20% but did not affect MEI. Glucose infusion did not affect DMI or MEI. Treatment effects on DMI and MEI were consistent with their expected effects on hepatic oxidation. Depression of feed intake in diets containing highly fermentable starch is likely because of differences in hepatic metabolism.

Temporal effects of ruminal propionic acid infusion on feeding behavior of Holstein cows in the postpartum period

The objective of this study was to determine the temporal effects of intraruminal infusion of propionic acid at the initiation of meals on feeding behavior of cows in the postpartum period. Propionic acid derived from ruminal fermentation can reduce energy intake of dairy cows. The suppression of appetite by propionic acid is likely caused by a signal related to the hepatic oxidation of fuels. Greater propionate flux to the liver is expected to result in faster oxidation of acetyl coenzyme A, which can stimulate satiety and reduce feed intake. Therefore, the rate of propionate supply to the liver, within the timeframe of meals, might be an important limitation to feed intake. Our hypothesis was that faster rate of propionate infusion during meals would decrease meal size and feed intake by decreasing the time required to stimulate satiety within a meal. Six ruminally cannulated, multiparous Holstein cows in the postpartum period were used in a duplicated 3 × 3 Latin square design experiment balanced for carryover effects. Treatments included control (no infusion) or 1.25 mol of propionic acid infused over 5 min (FST) or 15 min (SLW) at each meal. Infusions were initiated at the conditioned meal at feeding (1200 h) and were triggered at each spontaneous meal for 22 h. Contrary to our hypothesis, SLW decreased meal size 29% (0.87 vs. 1.23 kg of dry matter) compared with FST, and FST decreased meal frequency 27% (8.5 vs. 11.2 per d) compared with SLW. Dry matter intake was similar between FST and SLW, but propionic acid decreased dry matter intake 46% compared with control. A potential explanation is that FST resulted in greater liver bypass of propionate compared with SLW, extending anaplerosis of the tricarboxylic acid cycle, hepatic oxidation of acetyl coenzyme A, and satiety over a longer time after meals.

Increased anaplerosis of the tricarboxylic acid cycle decreased meal size and energy intake of cows in the postpartum period

The objective of this study was to determine the effects of anaplerosis of the tricarboxylic acid cycle on feeding behavior and energy intake of cows in the postpartum period. We infused propionic acid (PA) and glycerol (GL) continuously into the abomasum and hypothesized that PA will decrease meal size and energy intake compared with GL because PA enters the tricarboxylic acid cycle, likely stimulating oxidation of acetyl CoA and satiety compared with GL. Three experiments (Exp.) were conducted using 20 Holstein cows between 3 and 22 d postpartum (8 cows in Exp. 1 and 6 cows each for Exp. 2 and 3). Treatments were compared using isoenergetic (Exp. 1, 193 kcal/h) and isomolar (Exp. 2, ∼0.5 mol/h) continuous infusions of PA (99.5%) and GL (99.7%) to the abomasum using a double crossover design with four 2-d infusion periods each, and 2 mol of PA or GL pulse-dosed to the abomasum using a crossover design (Exp. 3). Treatment sequences were assigned alternately to cows based upon date of parturition. Feeding behavior was recorded by a computerized data acquisition system for Exp. 1 and 2. Propionic acid decreased dry matter intake (DMI) compared with GL 16.7 and 23.4% in Exp. 1 and 2, respectively. The decrease in DMI was because PA decreased meal size compared with GL by 12.6 and 15.3% in Exp. 1 and 2, respectively. Propionic acid decreased total metabolizable energy intake (diet plus treatment infusions) compared with GL for both experiments. Compared with PA, GL increased plasma glucose and insulin concentrations for Exp. 2 only. In Exp. 3, PA decreased hepatic acetyl CoA content 34%, whereas GL increased hepatic acetyl CoA content 32%, resulting in lower hepatic acetyl CoA content for PA compared with GL at 30 min (18.0 vs. 36.9 nmol/g), which persisted at 60 min after dosing (21.9 vs. 32.8 nmol/g). Consistent with our hypothesis, the obligatory anaplerotic metabolite PA decreased meal size, DMI, and total metabolizable energy intake compared with GL, likely because of differences in their hepatic metabolism.

The control of short-term feed intake by metabolic oxidation in late-pregnant and early lactating dairy cows exposed to high ambient temperatures

The objective of the present study was to integrate the dynamics of feed intake and metabolic oxidation in late pregnant and early lactating Holstein cows under heat stress conditions. On day 21 before parturition and again on day 20 after parturition, seven Holstein cows were kept for 7days at thermoneutral (TN) conditions (15°C; temperature–humidity-index (THI)=60) followed by a 7day heat stress (HS) period at 28°C (THI=76). On the last day of each temperature condition, gas exchange, feed intake and water intake were recorded every 6min in a respiration chamber. Pre- and post-partum cows responded to HS by decreasing feed intake. The reduction in feed intake in pre-partum cows was achieved through decreased meal size, meal duration, eating rate and daily eating time with no change in meal frequency, while post-partum cows kept under HS conditions showed variable responses in feeding behavior. In both pre- and post-partum cows exposed to heat stress, daily and resting metabolic heat production decreased while the periprandial respiratory quotient (RQ) increased. The prolonged time between meal and the postprandial minimum in fat oxidation and the postprandial RQ maximum, respectively, revealed that HS as compared to TN early-lactating cows have slower postprandial fat oxidation, longer feed digestion, and thereby showing a shift from fat to glucose utilization.

Yeast product supplementation modulated feeding behavior and metabolism in transition dairy cows

Yeast supplementation has been shown to increase feed intake and production in some studies with early lactation dairy cows, but the mechanisms underlying such an effect remain unknown. The objective of this study was to assess the effects of supplementing a yeast product derived from Saccharomyces cerevisiae on production, feeding behavior, and metabolism in cows during the transition to lactation. Forty multiparous Holstein cows were blocked by expected calving date and randomly assigned within block to 1 of 4 treatments (n=10) from 21 d before expected calving to 42 d postpartum. Rations were top-dressed with a yeast culture plus enzymatically hydrolyzed yeast (YC-EHY; Celmanax, Vi-COR Inc., Mason City, IA) at the rate of 0, 30, 60, or 90g/d throughout the experiment. Dry matter and water intake, feeding behavior, and milk production were monitored. Plasma samples collected on −21, −7, 1, 4, 7, 14, 21, and 35 d relative to calving were analyzed for glucose, β-hydroxybutyrate, and nonesterified fatty acids. Data were analyzed using mixed models with repeated measures over time. Pre- or postpartum dry matter intake and water intake did not differ among treatments. Quadratic dose effects were observed for prepartum feeding behavior, reflecting decreased meal size, meal length, and intermeal interval, and increased meal frequency for cows received 30 and 60g/d of YC-EHY. Postpartum feeding behavior was unaffected by treatments. Milk yields were not affected (45.3, 42.6, 47.8, and 46.7kg/d for 0, 30, 60, and 90g/d, respectively) by treatments. Tendencies for increased percentages of milk fat, protein, and lactose were detected for cows receiving YC-EHY. Supplementing YC-EHY increased plasma β-hydroxybutyrate and tended to decrease (quadratic dose effect) glucose but did not affect nonesterified fatty acids. Yeast product supplementation during the transition period did not affect milk production and dry matter intake but modulated feeding behavior and metabolism.

Obesity-linked homologues TfAP-2 and Twz establish meal frequency in Drosophila melanogaster.

In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the number of meals in adult flies. Loss of TfAP-2 or Twz in octopaminergic neurons increased the size of individual meals, while overexpression of TfAP-2 significantly decreased meal size and increased feeding frequency. Of note, our study reveals that TfAP-2 and Twz regulate octopamine signaling to initiate feeding; then octopamine, in a negative feedback loop, induces expression of Dsk to inhibit consummatory behavior. Intriguingly, we found that the mouse TfAP-2 and Twz homologues, AP-2β and Kctd15, co-localize in areas of the brain known to regulate feeding behavior and reward, and a proximity ligation assay (PLA) demonstrated that AP-2β and Kctd15 interact directly in a mouse hypothalamus-derived cell line. Finally, we show that in this mouse hypothalamic cell line AP-2β and Kctd15 directly interact with Ube2i, a mouse sumoylation enzyme, and that AP-2β may itself be sumoylated. Our study reveals how two obesity-linked homologues regulate metabolic homeostasis by modulating consummatory behavior.

Tu1805 The Mid-Fragment Nesfatin-130-59 Injected Intracerebroventricularly Induces a Long-Lasting Reduction in Food Intake by Decreasing Meal Size in Rats

G A A b st ra ct s cortex (ACC) after NES (Figure 2). Significant differences seen after NES when HC and CVS patients were compared included the R VPM to the R MCC, L lateral ACC and L dorsal posterior insula, the L VPM to the L and R MCC, the L LP to the R MCC and the R VPL to the L dorsal and ventral anterior insula and the L ACC. CONCLUSIONS: NES affects TCC and TIC differently in CVS compared to HC. In that, NES affects TCC in both CVS and HC. Contrary to HC, NES does not alter TIC in CVS. This finding provides evidence for an altered central control mechanism in CVS patients.

Systemic treatment with d-fenfluramine, but not sibutramine, blocks cue-induced reinstatement of food-seeking behavior in the rat

Individuals struggling with obesity often have difficulty maintaining dietary regimens. One source of dietary relapse is the reinstatement of previous feeding behaviors following the presentation of cues indicating the availability of palatable but highly caloric food reward. The drugs fenfluramine and sibutramine have previously been prescribed because they enhance satiety mechanisms and decrease meal size. However, it is unclear whether these anorectic agents are also effective in blocking the cue-induced reinstatement of food-seeking behaviors. In these three experiments, we compared the effects of systemic treatment of d-fenfluramine (3mg/kg; N=10) and sibutramine (3mg/kg; N=11) with that of the D1 antagonist SCH 23390 (6μg/kg; N=11) at a dose that has previously been shown to attenuate cue-induced reinstatement. d-Fenfluramine treatment blocked the cue's ability to reinstate lever pressing as compared to the saline injection day. In contrast, sibutramine had no effect on cue-induced reinstatement; all animals reinstated their lever pressing during the first reinstatement test, and this was unaffected by sibutramine treatment. SCH 23390 treatment did not significantly reduce cue-induced reinstatement in this set of experiments. The results suggest that the motivational effects of d-fenfluramine is not limited to the promotion of satiety once a meal has been initiated, and demonstrate that some anorectic treatments may inhibit the effectiveness of conditioned cues to elicit relapse of food-seeking behavior.

The snacking rat as model of human obesity: effects of a free-choice high-fat high-sugar diet on meal patterns

Rats subjected to a free-choice high-fat high-sugar (fcHFHS) diet persistently overeat, exhibit increased food-motivated behavior and become overtly obese. Conversely, several studies using a non-choice (nc) high-energy diet showed only an initial increase in food intake with unaltered or reduced food-motivated behavior. This raises the question of the importance of choice in the persistence of hyperphagia in rats on a fcHFHS diet. Meal patterns, food intake and body weight gain were studied in male Wistar rats on free-choice diets with fat and/or sugar and in rats on nc diets with fat and sugar (custom made with ingredients similar to the fcHFHS diet). Rats on a ncHFHS diet initially overconsumed, but reduced intake thereafter, whereas rats on a fcHFHS diet remained hyperphagic. Because half of the sugar intake in the fcHFHS group occurred during the inactive period, we next determined whether sugar intake during the light phase was a necessary requirement for hyperphagia, by restricting access to liquid sugar to either the light or dark period with unlimited access to fat and chow. Results showed that hyperphagia occurred irrespective of the timing of sugar intake. Meal pattern analysis revealed consumption of larger but fewer meals in the ncHFHS group, as well as the fcHF group. Interestingly, meal number was increased in all rats drinking liquid sugar (whether on a fcHFHS or a fcHS diet), whereas a compensatory decrease in meal size was only observed in the fcHS group, but not the fcHFHS group. We hereby show the importance of choice in the observation of fcHFHS diet-induced hyperphagia, which results in increases in meal number due to sugar drinking without any compensatory decrease in meal size. We thus provide a novel dietary model in rats that mimics important features of human overconsumption that have been ignored in rodent models of obesity.

The expression of MC4Rs in D1R neurons regulates food intake and locomotor sensitization to cocaine

While it is known that mice lacking melanocortin 4 receptor (MC4R) expression develop hyperphagia resulting in early-onset obesity, the specific neural circuits that mediate this process remain unclear. Here, we report that selective restoration of MC4R expression within dopamine-1 receptor-expressing neurons [MC4R/dopamine 1 receptor (D1R) mice] partially blunts the severe obesity seen in MC4R-null mice by decreasing meal size, but not meal frequency, in the dark cycle. We also report that both acute cocaine-induced anorexia and the development of locomotor sensitization to repeated administration of cocaine are blunted in MC4R-null mice and normalized in MC4R/D1R mice. Neuronal retrograde tracing identifies the lateral hypothalamic area as the primary target of MC4R-expressing neurons in the nucleus accumbens. Biochemical studies in the ventral striatum show that phosphorylation of DARPP-32(Thr) (-34) and GluR1(Ser) (-845) is diminished in MC4R-null mice after chronic cocaine administration but rescued in MC4R/D1R mice. These findings highlight a physiological role of MC4R-mediated signaling within D1R neurons in the long-term regulation of energy balance and behavioral responses to cocaine.

Clinical Ramifications of Giant Paraesophageal Hernias Are Underappreciated: Making the Case for Routine Surgical Repair

We propose that the symptoms associated with paraesophageal hernia (PEH) are more diverse than previously suggested, and symptoms and clinical manifestations correlate to the anatomy of the hernia. Patients undergoing surgery for PEH were reviewed from a prospective, institutional review board-approved, single-center database. Presenting symptoms, anatomy of the PEH, demographics, and outcomes were analyzed from 2000 to 2010. Presenting symptoms were assessed for incidence and improvement after surgery. Size and configuration of the PEH were assessed with respect to presenting symptoms. The study included 270 consecutive patients, 63% were female, and the median age was 70 years (range, 39 to 94 years). The most common presenting symptoms were heartburn in 175 patients (65%), early satiety in 136 patients (50%), chest pain in 130 patients (48%), dyspnea in 130 patients (48%), dysphagia in 129 patients (48%), regurgitation in 128 patients (47%), and anemia in 112 patients (41%). Two hundred sixty-nine patients (99.6%) had at least one symptom; the median number of symptoms was 4 (range, 0 to 10). The type of PEH was II (n=10), III (n=206), and IV (n=54), and the percent intrathoracic stomach was less than 50% (n=33), 50% to 74% (n=86), 75% to 99% (n=55), and 100% (n=96). Paraesophageal hernia type was significantly associated with heartburn (type II/III; p=0.005) and dyspnea (type IV; p=0.007). Significant associations included lower percent intrathoracic stomach with regurgitation (p=0.04); higher percent intrathoracic stomach with early satiety (p=0.02), decreased meal size (p=0.007), and dyspnea (p<0.001); and 50% to 74% intrathoracic stomach with anemia (p=0.001). With a median postoperative follow-up of 103 days, symptoms were subjectively better in patients with dyspnea (67%), early satiety (79%), regurgitation (92%), dysphagia (81%), chest pain (76%), and heartburn (93%). Paraesophageal hernia is associated with a greater diversity of symptomatic presentation than previously thought. Asymptomatic patients are rare, and size and configuration of the hernia are associated with specific symptoms. Patients with large PEHs should be assessed by an experienced surgeon for elective repair.