Mechanisms Regulating Food Intake Research Articles

When should I eat: A circadian view on food intake and metabolic regulation.

The circadian clock is a hierarchical timing system regulating most physiological and behavioral functions with a period of approximately 24 h in humans and other mammalian species. The circadian clock drives daily eating rhythms that, in turn, reinforce the circadian clock network itself to anticipate and orchestrate metabolic responses to food intake. Eating is tightly interconnected with the circadian clock and recent evidence shows that the timing of meals is crucial for the control of appetite and metabolic regulation. Obesity results from combined long-term dysregulation in food intake (homeostatic and hedonic circuits), energy expenditure, and energy storage. Increasing evidence supports that the loss of synchrony of daily rhythms significantly impairs metabolic homeostasis and is associated with obesity. This review presents an overview of mechanisms regulating food intake (homeostatic/hedonic) and focuses on the crucial role of the circadian clock on the metabolic response to eating, thus providing a fundamental research axis to maintain a healthy eating behavior.

Evidence of gastrointestinal sensing and gut-brain communication in rainbow trout (Oncorhynchus mykiss) in response to the aqueous extract of fishmeal and its free amino acid fraction

Using rainbow trout (Oncorhynchus mykiss) as a model, we aimed to obtain information about the gastrointestinal tract (GIT) amino acid sensing capacity and hormone production along regions of the GIT, in response to proline (Pro), to a solution of free amino acids (FAA) mimicking the composition of a fishmeal (FM) aqueous extract (FM-FAA), or to the whole FM aqueous extract (FM-AQE). In addition, we evaluated central responses (in hypothalamus) in mechanisms regulating food intake, 2 h following intragastric administration of these treatments. The presence of Pro in the GIT elicited changes in amino acid sensing systems and in the production of GIT hormones, especially in the more proximal regions in parallel with an anorectic response in hypothalamus. The intragastric administration of FM-AQE induced increased production of the anorectic hormones peptide tyrosine-tyrosine (PYY) and cholecystokinin (CCK) that occurred 20 min post-treatment in the proximal and middle intestine of this treatment. These changes occurred in parallel with an anorectic response in the hypothalamus 2 h post-treatment. The treatment with FM-FAA elicited a comparable anorectic response in the hypothalamus at 2 h post-treatment, which was associated however with a more complex response in the GIT. This included a comparable increased production of the anorectic hormones PYY and CCK in the proximal and middle intestine, but also a decreased production of the orexigenic hormone ghrelin (GHRL) in the stomach, 20 min after FM-FAA administration. These effects were also accompanied by some changes in parameters related to amino acid sensing systems mediated by receptors, which were not observed in the FM-AQE treatment. Overall, results indicate that all treatments elicited a response in elements of gut sensing mechanisms and gut-brain axis, despite important differences in the specific genes (likely having different substrate specificities), GIT areas and times in which responses were observed.

Case report Liraglutid and insuline resistance

Weight reduction in patients with cardiovascular (CV) diseases and concurrent overweight or obesity brings a fundamental improvement in health and prognosis of such diseases, a proven reduction in mortality and morbidity, and is associated with a reduction in pharmacotherapy and the number of hospitalizations, therefore, it is also economically effective. With the current growing trend in population, obesity also becomes a population risk factor that is more significant than smoking, and a leading cause of preventable diseases. From this point of view, the availability of a new effective anti-obesity medication is very welcome, in particular, liraglutide elegantly interferes with the physiological mechanisms regulating food intake. In addition, it reduces the risk of developing diabetes and has anti- atherogenic effects. At the obese diabetic 2 type patients on insulin treatment often resistance develops and in spite of high insuline dosage inadequate control of glucose and HbA1c levels are obvious. We present the extreme case on this topic down: May 2013: first examination dated in our database of cardiology care dept. for out patients, 65 years old man, weight 144 kg, height 178 cm, waist circumferrence 143cm. His history: arterial hypertension since 1993, diabetes 2 type since 2008 on peroral treatment, paroxysmal atrial fibrilation since March 2013, diameter of the left atrium 50mm on ECHO, invasive coronarography negat. Therapy: telmisartan, metoprolol, nitrendipin, warfarin, propafenon, digoxin, spironolacton, statin. November 2013: effect of therapeutic lifestyle changes: regular sinus rhythm, weight 133kg, waist circumferrence 134cm, spironolacton substituted by eplerenon (asymetric gynecomastia), digoxin ex May 2014: weight 126kg, September 2014: atrial fibrilation, propafenon substituted by flekainid, then atrial flutter, switch from flekainid to amiodaron and digoxin, warfarin substituted by apixaban February 2015: sinus rhythm , weight 129kg December 2015: weight 140kg, BP 170/90 mmHg, atrial flutter with a-v blockage 4:1, ankle oedema on both sides, Hb 115g/l, urinary acid 499umol/l, creatinin 119 umol/l, added allopurinol, urapidil, furosemid May 2017: intensification of the diabetes treatment, added insulin application, dosage escalation during the next years, on ECHO: left atriium diameter 52mm, left ventricle diameter 62mm, systolic function of the left ventricle preserved, moderate mitral and tricuspidal regurgitation December 2017: sinus bradycardia 46/min, amiodaron and digoxin ex, sick sinus syndrom brady-tachycardia form, hepatomegaly July 2018: bariatric procedure contraindicated by surgeon because of age and health status December 2018: creatinin 169umol/l, urinary acid 652umol/l October 2019: weight 158 kg, hospitalisation for heart failúre, confirmed by increased NT- BNP level, therapeutic changes from sartan to ARNI, from warfarin to apixaban, increased furosemid dosage. February 2021: weight 159kg, O2 peripheral saturation 93%, start of partial fasting (8:16) May 2021: signifficant dyspnoe, NYHA III, ECHO: left atrium diameter 56mm, left ventricle diameter 70mm, EF of the left ventricle 0,50, E/A 0,7 March 2022: attempt to implantate permanent cardiostimulation device unsuccesfull because of anatomic venous abnormalities. Brain MRI: postischemic frontal area defect right side Creatinin 220 umol/l, kalium 5,4 mmol/l, Hb 121 g/l, diabetic nephropathy. Weight 160kg. Added iron supplement. In spite of high insulin dosage (Humalog 3x20 units and basal 2x50 units) 160 units per day the glucose level were around 20mmol/l July 2022: weight 161 kg, starting of liraglutid daily application of 0,6mg s.c., dosage escalation every week to 1,2, 2,4, 3,0 mg. October 2022: hunger feeling was signifficantly reduced, eating of smaller portions, without craving between main time schedule of eating. Weight reduced to 151kg during first 3 months of liraglutid application (cca minus 100g per day), insulin dosage was reduced to 60 units daily (Humalog ex, basal insulin reduced to 60 units) what was accompanied by signifficant glucose level reduction to around 8 mmol/l. Creatinin level was 166 umol/l, acidum uricum level was 323 umol/l. January 2023: weight 157kg, fat content 50%, water content 40%. ECHO: left ventricle diameter 60mm, EF 0,5, left atrium diameter 54mm, tricuspidal regurgitation not detected, E/A 0,7. creatinin 128 umol/l , kalium 4,5 mmol/l.

The ghrelin system follows a precise post-natal development in mini-pigs that is not impacted by dietary medium chain fatty-acids.

The ghrelin-ghrelin receptor (GHSR1) system is one of the most important mechanisms regulating food intake and energy balance. To be fully active, ghrelin is acylated with medium-chain fatty acids (MCFA) through the ghrelin-O-acetyl transferase (GOAT). Several studies reported an impact of dietary MCFA on ghrelin acylation in adults. Our study aimed at describing early post-natal development of the ghrelin system in mini-pigs as a model of human neonates and evaluating the impact of dietary MCFA. Suckled mini-pigs were sacrificed at post-natal day (PND) 0, 2, 5, and 10 or at adult stage. In parallel, other mini-pigs were fed from birth to PND10 a standard or a dairy lipid-enriched formula with increased MCFA concentration (DL-IF). Plasma ghrelin transiently peaked at PND2, with no variation of the acylated fraction except in adults where it was greater than during the neonatal period. Levels of mRNA coding pre-proghrelin (GHRL) and GOAT in the antrum did not vary during the post-natal period but dropped in adults. Levels of antral pcsk1/3 (cleaving GHRL into ghrelin) mRNA decreased significantly with age and was negatively correlated with plasma acylated, but not total, ghrelin. Hypothalamic ghsr1 mRNA did not vary in neonates but increased in adults. The DL-IF formula enriched antral tissue with MCFA but did not impact the ghrelin system. In conclusion, the ghrelin maturation enzyme PCSK1/3 gene expression exhibited post-natal modifications parallel to transient variations in circulating plasma ghrelin level in suckling piglets but dietary MCFA did not impact this post-natal development.

Exercise increases NPY/AgRP and TH neuron activity in the hypothalamus of female mice.

Recent evidence identifies a potent role for aerobic exercise to modulate the activity of hypothalamic neurons related to appetite; however, these studies have been primarily performed in male rodents. Since females have markedly different neuronal mechanisms regulating food intake, the current study aimed to determine the effects of acute treadmill exercise on hypothalamic neuron populations involved in regulating appetite in female mice. Mature, untrained female mice were exposed to acute sedentary, low- (10 m/min), moderate- (14 m/min), and high (18 m/min)-intensity treadmill exercise in a randomized crossover design. Mice were fasted 10 h before exercise, and food intake was monitored for 48 h after bouts. Immunohistochemical detection of cFOS was performed 3 h post-exercise to determine the changes in hypothalamic neuropeptide Y (NPY)/agouti-related peptide (AgRP), pro-opiomelanocortin (POMC), tyrosine hydroxylase (TH), and SIM1-expressing neuron activity concurrent with the changes in food intake. Additionally, stains for pSTAT3tyr705 and pERKthr202/tyr204 were performed to detect exercise-mediated changes in intracellular signaling. Briefly, moderate- and high-intensity exercises increased 24-h food intake by 5.9 and 19%, respectively, while low-intensity exercise had no effects. Furthermore, increases in NPY/AgRPARC, SIM1PVN, and TH neuron activity were observed 3 h after high-intensity exercise, with no effects on POMCARC neurons. While no effects of exercise on pERKthr202/tyr204 were observed, pSTAT3tyr705 was elevated specifically in NPY/AgRP neurons 3 h post-exercise. Overall, aerobic exercise increased the activity of several appetite-stimulating neuron populations in the hypothalamus of female mice, which may provide insight into previously reported sexual dimorphisms in post-exercise feeding.

Asperuloside Enhances Taste Perception and Prevents Weight Gain in High-Fat Fed Mice.

Asperuloside is an iridoid glycoside found in many medicinal plants that has produced promising anti-obesity results in animal models. In previous studies, three months of asperuloside administration reduced food intake, body weight, and adipose masses in rats consuming a high fat diet (HFD). However, the mechanisms by which asperuloside exerts its anti-obesity properties were not clarified. Here, we investigated homeostatic and nutrient-sensing mechanisms regulating food intake in mice consuming HFD. We confirmed the anti-obesity properties of asperuloside and, importantly, we identified some mechanisms that could be responsible for its therapeutic effect. Asperuloside reduced body weight and food intake in mice consuming HFD by 10.5 and 12.8% respectively, with no effect on mice eating a standard chow diet. Fasting glucose and plasma insulin were also significantly reduced. Mechanistically, asperuloside significantly reduced hypothalamic mRNA ghrelin, leptin, and pro-opiomelanocortin in mice consuming HFD. The expression of fat lingual receptors (CD36, FFAR1-4), CB1R and sweet lingual receptors (TAS1R2-3) was increased almost 2-fold by the administration of asperuloside. Our findings suggest that asperuloside might exert its therapeutic effects by altering nutrient-sensing receptors in the oral cavity as well as hypothalamic receptors involved in food intake when mice are exposed to obesogenic diets. This signaling pathway is known to influence the subtle hypothalamic equilibrium between energy homeostasis and reward-induced overeating responses. The present pre-clinical study demonstrated that targeting the gustatory system through asperuloside administration could represent a promising and effective new anti-obesity strategy.

Post-natal development of the ghrelin system and impact of medium-chain fatty acid-enriched formula feeding in Yucatan mini-pigs

Introduction The ghrelin-ghrelin receptor system is one of the most important mechanisms regulating food intake, energy balance and metabolism. Despite the growing interest on nutritional programming of eating disorders, post-natal development of the ghrelin system is currently poorly explored. Moreover, to be fully active, ghrelin must be acylated with medium-chain fatty acids (MCFA) via gastric enzymes (ghrelin-O-acetyl transferase (GOAT), convertase 1/3 (PCSK1/3)). Several reports described dietary modulation of this ghrelin acylation. Therefore, our study aimed at describing early post-natal development of the ghrelin system in mini-pigs as a model of human neonates and the impact of formula-feeding with either a standard or a MCFA-enriched formula on this development. Methods 36 sow-fed piglets were sacrificed 1 h after suckling at post-natal day (PND) 0, 2, 5 and 10. In parallel, 18 piglets were fed from birth to PND10 either a standard infant formula (STD-IF) or a dairy lipid -enriched formula to increase MCFA concentration (DL-IF, MCFA 4.7% of total fatty acid vs. 0.1% in STD-IF) and sacrificed 1 h after their last meal. Results Levels of pre-proghrelin (GHRL) and GOAT mRNA in the antrum did not vary with age (P = 0.79), while that of PCSK1/3 dropped by 50% between PND0 and 2 and slightly re-increased thereafter (P 0.05) but increased GOAT mRNA (+ 60%, P = 0.05). Total and acylated ghrelin plasma concentration were not affected by STD-IF feeding (P > 0.05). DL-IF feeding increased antrum MCFA concentration by 354% (P = 0.009) compared to suckling animals but had not impact on GHRL and PCSK1/3 antral mRNA levels (P > 0.05) nor on plasma total or acylated ghrelin levels (P > 0.05). GOAT mRNA level in MCFA-IF-fed piglets remained significantly greater than in suckling animals (+ 55%, P = 0.03). Plasma acylated/total ghrelin ratio and GOAT mRNA level correlated positively with MCFA concentration in gastric content (r = 0.565, P = 0.004 and r = 0.505, P = 0.01, respectively) while GHRL and PCSK1/3 mRNA levels correlated positively with MCFA concentration in gastric tissue (r = 0.567, P = 0.004 and r = 0.459, P = 0.02, respectively). Conclusion The ghrelin maturation enzyme PCSK1/3 gene expression exhibited transient post-natal modifications in parallel with transient variations in circulating plasma ghrelin level in suckling piglets. Formula feeding slightly impacted GOAT mRNA level with no significant change in circulating ghrelin levels, irrespective of the type of formula tested.

Perinatal exposure to bisphenol A (BPA) impairs neuroendocrine mechanisms regulating food intake and kisspetin system in adult male rats. Evidences of metabolic disruptor hypothesis

Bisphenol A (BPA) is a compound used in the polymerization of plastic polycarbonates. It is an endocrine disruptor and it has been postulated to be an obesogen. Our objective was to determine the influence of perinatal exposure to BPA on body weight, hormone levels, metabolic parameters and hypothalamic signals that regulate food intake and kisspeptin system in adult male rats. Male rats were exposed to 50 μg/kg/day of BPA or vehicle from day 9 of gestation to weaning in the drinking water. Since weaning, they were fed with control or high fat diet for 20 weeks. Perinatal exposure to BPA impaired glucose homeostasis, induced obesity and increased food intake in adult male rats altering hypothalamic signals, partially mimicking and/or producing an exacerbation of the effects of feeding fat diet. We also observed an increase in kisspeptin expression by BPA exposure. Evidences shown in this work support the metabolic disruptor hypothesis for BPA.

Daily memantine treatment blunts hedonic response to sucrose in rats.

Preclinical and clinical studies suggest the potential use of memantine in the treatment of binge eating disorder. The aim of this study was to further investigate the mechanisms by which memantine influences the motivational aspects of ingestion through the analysis of licking microstructure. To interpret treatment effects in relation to drug action at specific functionally relevant times, we compared the effect of two different administration schedules. Memantine was administered daily for a week, either 1h before or immediately after a 30-min daily session. The effects on the microstructure of licking for a 10% sucrose solution in rats were examined in the course of treatment and for 15days after treatment discontinuation. Treatment before testing reduced ingestion due to reduced burst size and increased latency in the first session. However, a progressive increase in burst number across sessions led to a full recovery of ingestion levels by the end of treatment. Daily post-session administration induced a dramatic decrease of activation of licking behaviour, indicated by reduced burst number, accompanied to reduced burst size. A slow recovery of ingestion took place after treatment discontinuation. These results suggest a reduced hedonic/reward evaluation response, an effect likely due to NMDA receptor blockade occurring during the testing time and support the hypothesis that memantine interferes with the hedonic/non-homeostatic mechanisms regulating food intake and food-seeking. The effect of post-session administration might be explained by the development of conditioned taste aversion.

How Satiating Are the 'Satiety' Peptides: A Problem of Pharmacology versus Physiology in the Development of Novel Foods for Regulation of Food Intake.

Developing novel foods to suppress energy intake and promote negative energy balance and weight loss has been a long-term but commonly unsuccessful challenge. Targeting regulation of appetite is of interest to public health researchers and industry in the quest to develop ‘functional’ foods, but poor understanding of the underpinning mechanisms regulating food intake has hampered progress. The gastrointestinal (GI) or ‘satiety’ peptides including cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) secreted following a meal, have long been purported as predictive biomarkers of appetite response, including food intake. Whilst peptide infusion drives a clear change in hunger/fullness and eating behaviour, inducing GI-peptide secretion through diet may not, possibly due to modest effects of single meals on peptide levels. We conducted a review of 70 dietary preload (DIET) and peptide infusion (INFUSION) studies in lean healthy adults that reported outcomes of CCK, GLP-1 and PYY. DIET studies were acute preload interventions. INFUSION studies showed that minimum increase required to suppress ad libitum energy intake for CCK, GLP-1 and PYY was 3.6-, 4.0- and 3.1-fold, respectively, achieved through DIET in only 29%, 0% and 8% of interventions. Whether circulating ‘thresholds’ of peptide concentration likely required for behavioural change can be achieved through diet is questionable. As yet, no individual or group of peptides can be measured in blood to reliably predict feelings of hunger and food intake. Developing foods that successfully target enhanced secretion of GI-origin ‘satiety’ peptides for weight loss remains a significant challenge.

Noncaloric Sweeteners Induce Peripheral Serotonin Secretion via the T1R3-Dependent Pathway in Human Gastric Parietal Tumor Cells (HGT-1).

The role of sweet taste in energy intake and satiety regulation is still controversial. Noncaloric artificial sweeteners (NCSs) are thought to help reduce energy intake, although little is known about their impact on the satiating neurotransmitter serotonin (5-HT). In the gastrointestinal (GI) tract, 5-HT regulates gastric acid secretion and gastric motility, both part of the complex network of mechanisms regulating food intake and satiety. This study demonstrated a stimulating impact compared to controls (100%) on 5-HT release in human gastric tumor cells (HGT-1) by the NCSs cyclamate (50 mM, 157% ± 6.3%), acesulfame potassium (Ace K, 50 mM, 197% ± 8.6%), saccharin (50 mM, 147% ± 6.7%), sucralose (50 mM, 194% ± 11%), and neohesperidin dihydrochalcone (NHDC, 1 mM, 201% ± 13%). Although these effects were not associated with the sweet taste intensity of the NCSs tested, involvement of the sweet receptor subunit T1R3 in the NCS-evoked response was demonstrated by mRNA expression of TAS1R3, co-incubation experiments using the T1R3 receptor antagonist lactisole, and a TAS1R3 siRNA knockdown approach. Analysis of the downstream signaling revealed activation of the cAMP/ERK/Ca2+ cascade. Co-treatment experiments with 10 mM glucose enhanced the 5-HT release induced by cyclamate, Ace K, saccharin, and sucralose, thereby supporting the enhancing effect of glucose on a NCS-mediated response. Overall, the results obtained identify NCSs as potent inducers of 5-HT release via T1R3 in human gastric parietal cells in culture and warrant in vivo studies to demonstrate their efficacy.

Comparative Physiology of Energy Metabolism: Fishing for Endocrine Signals in the Early Vertebrate Pool.

Energy is the common currency of life. To guarantee a homeostatic supply of energy, multiple neuro-endocrine systems have evolved in vertebrates; systems that regulate food intake, metabolism, and distribution of energy. Even subtle (lasting) dysregulation of the delicate balance of energy intake and expenditure may result in severe pathologies. Feeding-related pathologies have fueled research on mammals, including of course the human species. The mechanisms regulating food intake and body mass are well-characterized in these vertebrates. The majority of animal life is ectothermic, only birds and mammals are endotherms. What can we learn from a (comparative) study on energy homeostasis in teleostean fishes, ectotherms, with a very different energy budget and expenditure? We present several adaptation strategies in fish. In recent years, the components that regulate food intake in fishes have been identified. Although there is homology of the major genetic machinery with mammals (i.e., there is a vertebrate blueprint), in many cases this does not imply analogy. Although both mammals and fish must gain their energy from food, the expenditure of the energy obtained is different. Mammals need to spend vast amounts of energy to maintain body temperature; fishes seem to utilize a broader metabolic range to their advantage. In this review, we briefly discuss ecto- and endothermy and their consequences for energy balance. Next, we argue that the evolution of endothermy and its (dis-)advantages may explain very different strategies in endocrine regulation of energy homeostasis among vertebrates. We follow a comparative and evolutionary line of thought: we discuss similarities and differences between fish and mammals. Moreover, given the extraordinary radiation of teleostean fishes (with an estimated number of 33,400 contemporary species, or over 50% of vertebrate life forms), we also compare strategies in energy homeostasis between teleostean species. We present recent developments in the field of (neuro)endocrine regulation of energy balance in teleosts, with a focus on leptin.

A 12-week intervention with nonivamide, a TRPV1 agonist, prevents a dietary-induced body fat gain and increases peripheral serotonin in moderately overweight subjects.

A bolus administration of 0.15 mg nonivamide has previously been demonstrated to reduce energy intake in moderately overweight men. This 12-week intervention investigated whether a daily consumption of nonivamide in a protein-based product formulation promotes a reduction in body weight in healthy overweight subjects and affects outcome measures associated with mechanisms regulating food intake, e.g. plasma concentrations of (an)orexigenic hormones, energy substrates as well as changes in fecal microbiota. Nineteen overweight subjects were randomly assigned to either a control (C) or a nonivamide (NV) group. Changes in the body composition and plasma concentrations of satiating hormones were determined at fasting and 15, 30, 60, 90, and 120 min after a glucose load. Participants were instructed to consume 0.15 mg nonivamide per day in 450 mL of a milk shake additionally to their habitual diet. After treatment, a group difference in body fat mass change (-0.61 ± 0.36% in NV and +1.36 ± 0.38% in C) and an increase in postprandial plasma serotonin were demonstrated. Plasma metabolome and fecal microbiome read outs were not affected. A daily intake of 0.15 mg nonivamide helps to support to maintain a healthy body composition.

Impact of Liquid Sugar Reduction on Behavioral and Brain Responses to Food Viewing

Obesity is increasingly considered as a brain disease in which homeostatic mechanisms regulating food intake are overridden by hedonic drives towards consumption of foods high in fat and sugar. How added sugars from sugar‐sweetened beverages (SSBs) impact hedonic drives to foods, and whether artificial sweeteners have specific effects of their own remains unknown.We studied 14 high SSB consumers (8 men, 6 women) before and after 3 months of SSB replacement by artificially sweetened equivalents. Participants performed behavioral preference ratings on a 5‐point scale when presented with color images of solid foods differing in fat content (high‐ vs. low‐fat) and taste quality (savory vs. sweet). Moreover, the spatio‐temporal brain dynamics while viewing the food types were assessed using electroencephalography (EEG) and electrical neuroimaging analyses.Behavioral results show a significantly greater appreciation of savory foods, but decreased appreciation of sweet foods post‐SSB replacement. Brain responses reveal diet‐induced modulations in particular to low‐fat foods in areas involved in food valuation and cognitive control over food intake. That is, the replacement of liquid calories substantially influences responsiveness to solid calories, likely explaining changes in food intake behavior. Whether these effects are due to sugar reduction or to artificial sweeteners per se remains to be investigated.This work was supported by the Swiss National Science Foundation.

Central (mainly) actions of GPCRs in energy homeostasis/balance: view from the Chair.

To maintain a constant body weight, energy intake must equal energy expenditure; otherwise, there is a risk of overweight and obesity. The hypothalamus is one of the primary brain regions where multiple nutrient-related signals from peripheral and central sources converge and become integrated to regulate both short- and long-term nutritional states. The aim of the afternoon session of the 15th Annual International Symposium of the Laval University Obesity Research Chair held in Quebec City on 9 November 2012 was to present the most recent insights into the complex molecular mechanisms regulating food intake. The aims were to emphasize on the interaction between central and peripheral actions of some of the key players acting not only at the hypothalamic level but also at the periphery. Presentations were focused on melanocortin-3 receptor (MC3R) and melanin-concentrating hormone (MCH) as anorexigenic and orexigenic components of the hypothalamus, on endocannabinoid receptors, initially as a central neuromodulatory signal, and on glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) as peripheral signals. What becomes clear from these four presentations is that the regulation of food intake and energy homeostasis involves several overlapping pathways, and that we have only touched the tip of the iceberg. From the examples presented in this symposium, it could be expected that in the near future, in addition to a low-fat diet and exercise, a combination of appropriate peptides and small molecules is likely to become available to improve/facilitate the objectives of long-term maintenance of energy balance and body weight.

JAK-STAT and feeding

The regulation of energy balance requires a complex system to homeostatically maintain the adult body at a precise set point. The central nervous system, particularly the hypothalamus, plays a key role in integrating a variety of signals that can relay information about the body’s energy stores. As part of this system, numerous cytokines and hormones contribute to the regulation of food intake and energy homeostasis. Cytokines, and some hormones, are known to act through JAK-STAT intracellular signaling pathways. The hormone leptin, which plays a vital role in appetite regulation, signals through the JAK-STAT pathway, and it is through this involvement that the JAK-STAT pathway has become an established component in the mechanisms regulating food intake within the body. Emerging research, however, is now showing that this involvement of JAK-STAT is not limited to its activation by leptin. Furthermore, while the JAK-STAT pathway may simply act to transmit the anorectic signal of circulating factors, this intracellular signaling pathway may also become impaired when normal regulation of energy balance is disrupted. Thus, altered JAK-STAT signaling may contribute to the breakdown of the normal homeostatic mechanisms maintaining body weight in obesity.

Obesogenic phenotype of offspring of dams fed a high multivitamin diet is prevented by a post‐weaning high multivitamin or high folate diet

High multivitamin (10‐fold, HV) diet fed during pregnancy to Wistar rat dams increases food intake and characteristics of metabolic syndrome in their offspring weaned to the recommended vitamin (RV) AIN‐93G diet. This study determined if a HV or 10‐ fold high folate (HFol) diet fed to the offspring prevents the consequences of the HV gestational diet through epigenetic effects on hypothalamic mechanisms regulating food intake. Male offspring of dams fed the HV diet were weaned to RV, HV or HFol diets for 29 weeks, compared to those born to RV dams and weaned to the RV diet. Food intake, body weight, glucose response to a glucose load, hypothalamic gene expression and global DNA methylation were measured. Both the HV and HFol pup diets prevented the increase in food intake (5%, P=0.03), body weight (8%, P=0.0006) and glucose response (36%, P=0.02) found in offspring of HV dams weaned to the RV diet. Expression of proopiomelanocortin (160%, P=0.004) and brain‐derived neurotrophic factor (BDNF) (170%, P=0.02) was higher in pups fed the HV diet. The HFol pup diet also increased BDNF (130%, P=0.02), and lowered serotonin receptor 2A (60%, P=0.008) expression. Global DNA methylation was similar among groups. In conclusion, increasing the vitamin or folate content of the pup diet is effective in preventing the obesogenic phenotype in offspring of HV dams possibly due to post‐weaning modulation of food intake regulatory mechanisms.Grant Funding Source: Canadian Institutes of Health Research, Institute of Nutrition, Metabolism and Diabetes

Nesfatin‐1: a novel inhibitory regulator of food intake and body weight

The protein nucleobindin 2 (NUCB2) or NEFA (DNA binding/EF-hand/acidic amino acid rich region) was identified over a decade ago and implicated in intracellular processes. New developments came with the report that post-translational processing of hypothalamic NUCB2 may result in nesfatin-1, nesfatin-2 and nesfatin-3 and convergent studies showing that nesfatin-1 and full length NUCB2 injected in the brain potently inhibit the dark phase food intake in rodents including leptin receptor deficient Zucker rats. Nesfatin-1 also reduces body weight gain, suggesting a role as a new anorexigenic factor and modulator of energy balance. In light of the obesity epidemic and its associated diseases, underlying new mechanisms regulating food intake may be promising targets in the drug treatment of obese patients particularly as the vast majority of them display reduced leptin sensitivity or leptin resistance while nesfatin-1's mechanism of action is leptin independent. Although much progress on the localization of NUCB2/nesfatin-1 in the brain and periphery as well as on the understanding of nesfatin-1's anorexic effect have been achieved during the past three years, several important mechanisms have yet to be unraveled such as the identification of the nesfatin-1 receptor and the regulation of NUCB2 processing and nesfatin-1 release.

Sex steroid-induced inhibition of food intake in sea bass (Dicentrarchus labrax)

This study was conducted to test the sensitivity to gonadal steroids of the systems regulating food intake in sea bass. Animals were treated with silastic implants containing 17-beta-estradiol or testosterone. Self-feeding was recorded for 31 days using computerized demand feeders and unfed-pellet recovery systems. Both steroids strongly decreased self-feeding levels, feed efficiency and specific growth rates. The linear growth of fish treated with testosterone was higher than in 17-beta-estradiol treated fish. In the second experiment, fish were treated with lower 17-beta-estradiol doses and 11-keto-androstenedione, a precursor of the main fish androgen (11-keto-testosterone). The results demonstrated a dose-response effect of estrogen and no effect of non-aromatizable androgens on food intake or growth performance. The inhibitory effect of testosterone on food intake seems to be mediated by its aromatization to estradiol, while linear growth promotion is mediated by the androgen per se. Data suggest that gonadal steroids may be involved in the seasonal feeding pattern of sea bass. The results demonstrate the sensitivity of the mechanisms regulating food intake to estrogenic compounds and point to the risk of including feed containing estrogenic substances in fish diets as well as the risk involved in exposure to "estrogenic environments".

Activation of mesolimbic dopamine neurons during novel and daily limited access to palatable food is blocked by the opioid antagonist LY255582

An analog of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine series (LY255582) exhibits high in vitro binding affinity and antagonist potency for the mu-, delta-, and kappa-opioid receptors. In vivo, LY255582 exhibits potent effects in reducing food intake and body weight in several rodent models of obesity. In the present study, we evaluated the effects of LY255582 to prevent the consumption of a highly palatable (HP) diet (a high-fat/high-carbohydrate diet) both when the food was novel and following daily limited access to the HP diet. Additionally, we examined the effects of consumption of the HP diet and of LY255582 treatment on mesolimbic dopamine (DA) signaling by in vivo microdialysis. Consumption of the HP diet increased extracellular DA levels within the nucleus accumbens (NAc) shell. Increased DA in the NAc shell was not related to the quantity of the HP diet consumed, and the DA response did not habituate following daily scheduled access to the HP diet. Interestingly, treatment with LY255582 inhibited consumption of the HP diet and the HP diet-associated increase in NAc shell DA levels. Moreover, the increased HP diet consumption observed following daily limited access to the HP diet was completely prevented by LY255582 treatment. LY255582 may be a useful tool in understanding the neural mechanisms involved in the reinforcement mechanisms regulating food intake.