Central Regulation Of Appetite Research Articles

Micro/nanoplastics impair the feeding of goldfish by disrupting the complicated peripheral and central regulation of appetite

The ubiquitous presence of plastic particles in water bodies poses a potential threat to aquatic species. Although numerous adverse effects of microplastics (MPs) and nanoplastics (NPs) have been documented, their effects on fish feeding, one of the most important behaviors of animals, are far from being fully understood. In this study, the effects of MPs and NPs (at environmentally realistic levels) on fish food consumption and feeding behavior were assessed using goldfish (Carassius auratus) and polystyrene (PS) particles as representatives. In addition, to reveal the potential mechanisms, the effects of MPs and NPs on peripheral and central regulation of appetite were evaluated by examining appetite-regulation related intestinal, serous, and hypothalamic parameters. The results obtained indicated that the 28-day MP- and NP-exposure significantly impaired goldfish feeding by disrupting peripheral and central appetite regulation. Based on differences observed in their effects on the abovementioned behavioral, histological, and physiological parameters, MPs and NPs may interfere with appetite regulation in a size-dependent manner. Blocking the gastrointestinal tract and causing histopathological and functional damage to inner organs may be the main routes through which MPs and NPs disrupt appetite regulation. Our findings suggested that plastic particles exposure may have far-reaching effects on fish species through impaired feeding, which warrants further attention.

Pharmacological strategies for appetite modulation in eating disorders: a narrative review.

A substantial increase in the prevalence of eating disorders has been noticed over the past decades. Priority in the treatment of eating disorders is justifiably given to psychosocial interventions. However, it is also well known that centrally acting drugs can significantly affect appetite and food consumption. To narratively review the available neurobiological data on the mechanisms of central regulation of eating behavior as a rationale to summarize pharmacological strategies for appetite modulation in eating disorders. The authors have carried out a narrative review of scientific papers published from January 2013 to March 2023 in the PubMed and Web of Science electronic databases. Studies were considered eligible if they included data on the neurobiological mechanisms of appetite regulation or the results of clinical trials of centrally acting drugs in eating disorders. Relevant studies were included regardless of their design. Descriptive analysis was used to summarize the obtained data. The review included 51 studies. The available neurobiological and clinical data allowed us to identify the following pharmacological strategies for appetite modulation in eating disorders: serotonergic, catecholaminergic, amino acidergic and peptidergic. However, implementation of these data into clinical practice difficult due to an insufficient number of good-quality studies, which is particularly relevant for adolescents as there is a research gap in this population. The progress in neurobiological understanding of the mechanisms of central regulation of appetite opens opportunities for new pharmacotherapeutic approaches aimed at changing the patterns of eating behavior. Obviously, treatment of eating disorders is a much broader problem and cannot be reduced to the correction of eating patterns. Nevertheless, at certain stages of treatment, drug-induced modulation of appetite can play an important role among multi-targeted biological and psychosocial interventions. Translation of neurobiological data into clinical practice requires a large number of clinical studies to confirm the long-term efficacy and safety of pharmacotherapeutic approaches and to develop personalized algorithms for the treatment of various forms of eating disorders in different age groups.

Role of central adiponectin and its interactions with NPY and GABAergic systems on food intake in neonatal layer chicken

Background & AimAdiponectin is a member of the adipokine family and contributes to regulating energy homeostasis, reproduction, and various biological functions, such as insulin receptor signaling pathway sensitivity, mitochondrial biogenesis, oxidative metabolism, neurogenesis, and suppression of inflammation. This study aimed to investigate the effects of intracerebroventricular (ICV) injection of adiponectin and its interaction with the neuropeptide Y (NPY) and GABAergic systems on central appetite regulation in neonatal layer-type chickens. Materials & MethodsIn this study, 6 experiments were conducted, each of which included 4 experimental groups. In the first experiment, the chickens were injected with saline and adiponectin (20.73, 41.45, and 62.18 nmol). In the second experiment, saline, adiponectin (62.18 nmol), B5063 (NPY1 receptor antagonist, 2.12 nmol), and simultaneous injections of adiponectin and B5063 were performed. Experiments 3 to 6 were done in the same way to experiment 1, but the chickens were injected with SF22 (NPY2 receptor antagonist, 2.66 nmol), SML0891 (NPY5 receptor antagonist, 2.89 nmol), picrotoxin (GABAA receptor antagonist, 0.89 nmol), CGP54626 (GABAB receptor antagonist, 0.047 nmol) instead of B5063. Feed consumption was measured 120 min after the injection. ResultsA dose-dependent increase in appetite was observed after the injection of adiponectin (20.73, 41.45, and 62.18 nmol) (P < 0.05). The injection of B5063 + adiponectin attenuated the hyperphagic effect of adiponectin (P < 0.05). In addition, co-injection of picrotoxin and adiponectin significantly decreased adiponectin-induced hyperphagia (P < 0.05). In addition, adiponectin significantly increased the number of steps, jumps, exploratory food, pecks, and standing time, while decreasing sitting time and rest time (P < 0.05). ConclusionThese results suggest that the hyperphagic effects of adiponectin are probably mediated through NPY1 and GABAA receptors in neonatal layer-type chickens.

Central regulation of appetite in birds: Recent advances and future perspective

Understanding the mechanism of food intake is important for comprehending energy balance, obesity, and the body weight regulation. In particular, examining birds' appetite is critical for conservation efforts, managing human-bird interactions, and understanding the environmental implications of bird feeding practices. In this systematic review, using the PRISMA guideline, we investigated the mediators that were identified as factors affecting the birds' appetite in 2022 and 2023. In order to obtain the appropriate studies, suitable keywords were searched in the relevant electronic databases and an anthology of the desired articles was done. According to the findings, the central administration of adrenomedullin, apelin-13, lipopolysaccharide, neuromedins and spexin causes hypophagia in chickens, while the injection of adiponectin, neuropeptide W (NPW) and phonexin-14 increased the food intake of birds. Also, regarding the members of RF-amide peptide family, neuropeptide VF (NPVF) and neuropeptide FF (NPFF) weakened the food consumption of birds, while kisspeptin and prolactin-releasing peptide (PrRP) strengthened it. The effects observed in birds were similar to mammals in most cases, indicating the structural and general similarities in the regulatory mechanisms of these strains, on the other hand, the contradictory effects between the two species were probably caused by genetic differences. Finally, despite the progress made in identifying the factors and mechanisms involved in regulating the appetite of birds, it is recommended to conduct future studies using modern laboratory methods, especially cellular-molecular methods.

Sleep Deprivation and Central Appetite Regulation.

Research shows that reduced sleep duration is related to an increased risk of obesity. The relationship between sleep deprivation and obesity, type 2 diabetes, and other chronic diseases may be related to the imbalance of appetite regulation. To comprehensively illustrate the specific relationship between sleep deprivation and appetite regulation, this review introduces the pathophysiology of sleep deprivation, the research cutting edge of animal models, and the central regulatory mechanism of appetite under sleep deprivation. This paper summarizes the changes in appetite-related hormones orexin, ghrelin, leptin, and insulin secretion caused by long-term sleep deprivation based on the epidemiology data and animal studies that have established sleep deprivation models. Moreover, this review analyzes the potential mechanism of associations between appetite regulation and sleep deprivation, providing more clues on further studies and new strategies to access obesity and metabolic disease.

A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression.

Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here, we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTNTac1 neurons) and those that express corticotropin-releasing hormone (PSTNCRH neurons), and use a panel of genetically encoded tools in mice to show that PSTNTac1 neurons play an important role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTNTac1, but not PSTNCRH neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTNTac1 neurons, but not PSTNCRH neurons, reduces food intake in hungry mice. PSTNTac1 and PSTNCRH neurons project to distinct downstream brain regions, and stimulation of PSTNTac1 projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an anorexigenic role for PSTNTac1 neurons in the hormonal and central regulation of appetite.

The Role of Selenoprotein Tissue Homeostasis in MetS Programming: Energy Balance and Cardiometabolic Implications.

Selenium (Se) is an essential trace element mainly known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, as it is part of the catalytic center of 25 different selenoproteins. Some of them are related to insulin resistance (IR) and metabolic syndrome (MetS) generation, modulating reactive oxygen species (ROS), and the energetic sensor AMP-activated protein kinase (AMPK); they can also regulate the nuclear transcription factor kappa-B (NF-kB), leading to changes in inflammation production. Selenoproteins are also necessary for the correct synthesis of insulin and thyroid hormones. They are also involved in endocrine central regulation of appetite and energy homeostasis, affecting growth and development. MetS, a complex metabolic disorder, can appear during gestation and lactation in mothers, leading to energetic and metabolic changes in their offspring that, according to the metabolic programming theory, will produce cardiovascular and metabolic diseases later in life. However, there is a gap concerning Se tissue levels and selenoproteins’ implications in MetS generation, which is even greater during MetS programming. This narrative review also provides an overview of the existing evidence, based on experimental research from our laboratory, which strengthens the fact that maternal MetS leads to changes in Se tissue deposits and antioxidant selenoproteins’ expression in their offspring. These changes contribute to alterations in tissues’ oxidative damage, inflammation, energy balance, and tissue function, mainly in the heart. Se imbalance also could modulate appetite and endocrine energy balance, affecting pups’ growth and development. MetS pups present a profile similar to that of diabetes type 1, which also appeared when dams were exposed to low-Se dietary supply. Maternal Se supplementation should be taken into account if, during gestation and/or lactation periods, there are suspicions of endocrine energy imbalance in the offspring, such as MetS. It could be an interesting therapy to induce heart reprogramming. However, more studies are necessary.

The contribution of astrocytes to obesity-associated metabolic disturbances.

Obesity is a worldwide health, economic and social concern, despite efforts made to counteract the spreading wave of eating and nourishment-associated disorders. The review aims to show how the glial cells, astrocytes, contribute to the central regulation of appetite and energy metabolism. The hypothalamus is the brain center responsible for nutrients and nutritional hormone sensing, signal processing, and execution of metabolic and behavioral responses, directed at sustaining energy homeostasis. The astrocytes are endowed with receptors, transporters and enzymatic machinery responsible for glucose, lactate, fatty acids, ketone bodies, as well as leptin or ghrelin transport and metabolism, and that render them supporters and partners for neurons in governing the brain and body energy intake and expenditure. However, the role of astrocytes associated with brain energy metabolism reaches far beyond simple fuel contingent—they contribute to cognitive performance. The cognitive decline which often accompanies high fat- and/or high-calorie diets and correlates with neuroinflammation and astrogliosis, is a major concern. The last two decades of research enabled us to acknowledge the astroglia in obesity-associated dysfunctions and to investigate astrocytes as contributors to the pathology, as well as targets for therapy.

Central muscarinic receptor subtypes (M1 and M3) involved in carbacol-induced hypophagia in neonatal broiler chicken

Aim: Food intake regulated by a complex of physiologic mechanisms in the nervous system. Muscarinergic system has an important role in the central regulation of appetite in mammals, but there is no information for Muscarinic receptors in avian. The purpose of this study was to examine the effects of intracerebroventricular injection of carbachol (cholinergic agonist), Telenzepine (M1 receptor antagonist), AF-DX116 (M2 receptor antagonist), 4-DAMP (M3 receptor antagonist), and PD102807 (M4 receptor antagonist) on feeding behavior in 3-h food-deprived (FD3) neonatal broiler chicken.Materials and Methods: In experiment 1, chicken intracerebroventricular injected with carbachol (125, 250, and 500 nmol). In experiment 2, birds intracerebroventricular injected with telenzepine (125, 250, and 500 nmol). In experiments 3–5, birds intracerebroventricular injected with AF-DX 116 (125, 250, and 500 nmol), 4-DAMP (125, 250, and 500 nmol), and PD102807 (125, 250, and 500 nmol), respectively. In experiment 6, broilers intracerebroventricular injected with carbacol (500 nmol), co-injection of telenzepine (125 nmol)+carbacol (500 nmol), and 4-DAMP (125 nmol)+carbacol (500 nmol). In experiment 7, injection procedure was carbacol (500 nmol), co-injection of AF-DX116 (125 nmol)+carbacol (500 nmol), and PD102807 (125 nmol)+carbacol (500 nmol). Then, food intake measured until 120 min after injection.Results: According to the data, carbachol (250 and 500 nmol) significantly decreased food intake in comparison with control group (P < 0.05). Intracerebroventricular injection of telenzepine (250 and 500 nmol) and 4-DAMP (250 and 500 nmol) significantly increased food intake (P < 0.05). In addition, carbacol-induced hypophagia was significantly attenuated by co-injection of telenzepine + carbacol (P < 0.05). Also, co-injection of 4-DAMP + carbacol decreased the effect of carbacol on food intake (P < 0.05). However, AF-DX116 and PD102807 had no effect on hypophagia induced by carbacol (P > 0.05).Conclusion: These results suggest, hypophagic effect of muscarinergic system is mediated via M1 and M3 receptors in neonatal chicken.

Cholecystokinin Switches the Plasticity of GABA Synapses in the Dorsomedial Hypothalamus via Astrocytic ATP Release.

Whether synapses in appetite-regulatory brain regions undergo long-term changes in strength in response to satiety peptides is poorly understood. Here we show that following bursts of afferent activity, the neuromodulator and satiety peptide cholecystokinin (CCK) shifts the plasticity of GABA synapses in the dorsomedial nucleus of the hypothalamus of male Sprague Dawley rats from long-term depression to long-term potentiation (LTP). This LTP requires the activation of both type 2 CCK receptors and group 5 metabotropic glutamate receptors, resulting in a rise in astrocytic intracellular calcium and subsequent ATP release. ATP then acts on presynaptic P2X receptors to trigger a prolonged increase in GABA release. Our observations demonstrate a novel form of CCK-mediated plasticity that requires astrocytic ATP release, and could serve as a mechanism for appetite regulation.SIGNIFICANCE STATEMENT Satiety peptides, like cholecystokinin, play an important role in the central regulation of appetite, but their effect on synaptic plasticity is not well understood. The current data provide novel evidence that cholecystokinin shifts the plasticity from long-term depression to long-term potentiation at GABA synapses in the rat dorsomedial nucleus of the hypothalamus. We also demonstrate that this plasticity requires the concerted action of cholecystokinin and glutamate on astrocytes, triggering the release of the gliotransmitter ATP, which subsequently increases GABA release from neighboring inhibitory terminals. This research reveals a novel neuropeptide-induced switch in the direction of synaptic plasticity that requires astrocytes, and could represent a new mechanism by which cholecystokinin regulates appetite.

Endogenous GLP-1 alters postprandial functional connectivity between homeostatic and reward-related brain regions involved in regulation of appetite in healthy lean males: A pilotstudy.

Peripheral infusion of glucagon-like peptide-1 (GLP-1) can affect brain activity in areas involved in the regulation of appetite, including hypothalamic and reward-related brain regions. In contrast, the physiological role of endogenous GLP-1 in the central regulation of appetite has hardly been investigated. This was a randomized, cross-over trial that involved 12 healthy volunteers who received an intragastric (ig) glucose (gluc) load, with or without intravenous (iv) exendin9-39 (ex9-39; specific GLP-1 receptor antagonist). Functional magnetic resonance imaging was used to investigate the effect of endogenous GLP-1 on resting state functional connectivity (rsFC) between homeostatic and reward-related brain regions. Visual analogue scales were used to rate appetite-related sensations. Blood samples were collected for GI hormone measurements. Administration of iv-ex9-39/ig-gluc induced a significantly higher rsFC, relative to ig-gluc administration, between the hypothalamus and the left lateral orbitofrontal cortex (OFC) as well as the left amygdala (P ≤ .001, respectively). Administration of iv-ex9-39/ig-gluc induced a significantly higher rsFC, relative to ig-gluc administration, between the right nucleus accumbens and the right lateral OFC (P < .001). Administration of iv-ex9-39/ig-gluc induced a significantly lower rsFC, relative to ig-gluc administration, between the midbrain and the right caudate nucleus (P = .001). Administration of ig-gluc significantly decreased prospective food consumption and increased sensations of fullness compared to pre-infusion baseline (P = .028 and P = .019, respectively); these effects were not present in the iv-ex9-39/ig-gluc condition. This pilot trial provides preliminary experimental evidence that glucose-induced endogenous GLP-1 affects central regulation of appetite by modulating rsFC in homeostatic and reward-related brain regions in healthy lean male participants in a GLP-1 receptor-mediated fashion.

Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia.

Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.

Involvement of Gaba and Cannabinoid Receptors in Central Food Intake Regulation in Neonatal Layer Chicks: Role of CB1 and Gabaa Receptors

ABSTRACT Feeding behavior is regulated via a complex network which interacts via diverse signals from central and peripheral tissues. Endocannabinoids modulate release of GABA in a variety of regions of the central nervous system. Endocannabinoids and GABAergic system have an important role in the central regulation of appetite. Thus, the present study examines the possible interaction of central canabinoidergic and GABAergic systems on food intake in 3-h food-deprived (FD3) neonatal layer-type chicks. The results of this study showed that intracerebroventricular (ICV) injection of 2-AG (2-Arachidonoylglycerol, selective CB1 receptors agonist, 2µg) significantly increased food intake and this effect of 2-AG was attenuated by Picrotoxin (GABAA antagonist, 0.5µg) (P 0.05). Also, hyperphagic effect of CB65 (CB2 receptors agonist, 1.25µg) was not affected by Picrotoxin or CGP54626 (p>0.05). Moreover, the food intake of chicks was significantly increased by ICV injection of GABAA agonist (Gaboxadol, 0.2 µg) and SR141716A (CB1 receptors antagonist, 6.25µg) significantly decreased Gaboxadol-induced hyperphagia (P 0.05). These data showed there might be an interaction between central cannabinoidergic and GABAergic systems via CB1 and GABAA receptors in control of food intake in neonatal layer chicks.

Control of Appetite and Food Preference by NMDA Receptor and Its Co-Agonist d-Serine.

Obesity causes a significant negative impact on health of human beings world-wide. The main reason for weight gain, which eventually leads to obesity, is excessive ingestion of energy above the body’s homeostatic needs. Therefore, the elucidation of detailed mechanisms for appetite control is necessary to prevent and treat obesity. N-methyl-d-aspartate (NMDA) receptor is a post-synaptic glutamate receptor and is important for excitatory neurotransmission. It is expressed throughout the nervous system, and is important for long-term potentiation. It requires both ligand (glutamate) and co-agonist (d-serine or glycine) for efficient opening of the channel to allow calcium influx. d-serine is contained in fermented foods and marine invertebrates, and brain d-serine level is maintained by synthesis in vivo and supply from food and gut microbiota. Although the NMDA receptor has been reported to take part in the central regulation of appetite, the role of d-serine had not been addressed. We recently reported that exogenous d-serine administration can suppress appetite and alter food preference. In this review, we will discuss how NMDA receptor and its co-agonist d-seine participate in the control of appetite and food preference, and elaborate on how this system could possibly be manipulated to suppress obesity.

Association between cerebral cannabinoid 1 receptor availability and body mass index in patients with food intake disorders and healthy subjects: a [(18)F]MK-9470 PET study.

Although of great public health relevance, the mechanisms underlying disordered eating behavior and body weight regulation remain insufficiently understood. Compelling preclinical evidence corroborates a critical role of the endocannabinoid system (ECS) in the central regulation of appetite and food intake. However, in vivo human evidence on ECS functioning in brain circuits involved in food intake regulation as well as its relationship with body weight is lacking, both in health and disease. Here, we measured cannabinoid 1 receptor (CB1R) availability using positron emission tomography (PET) with [18F]MK-9470 in 54 patients with food intake disorders (FID) covering a wide body mass index (BMI) range (anorexia nervosa, bulimia nervosa, functional dyspepsia with weight loss and obesity; BMI range=12.5–40.6 kg/m2) and 26 age-, gender- and average BMI-matched healthy subjects (BMI range=18.5–26.6 kg/m2). The association between regional CB1R availability and BMI was assessed within predefined homeostatic and reward-related regions of interest using voxel-based linear regression analyses. CB1R availability was inversely associated with BMI in homeostatic brain regions such as the hypothalamus and brainstem areas in both patients with FID and healthy subjects. However, in FID patients, CB1R availability was also negatively correlated with BMI throughout the mesolimbic reward system (midbrain, striatum, insula, amygdala and orbitofrontal cortex), which constitutes the key circuit implicated in processing appetitive motivation and hedonic value of perceived food rewards. Our results indicate that the cerebral homeostatic CB1R system is inextricably linked to BMI, with additional involvement of reward areas under conditions of disordered body weight.

Anorexia-cachexia and obesity treatment may be two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15.

Anorexia-cachexia associated with cancer and other diseases is a common and often fatal condition representing a large area of unmet medical need. It occurs most commonly in advanced cancer and is probably a consequence of molecules released by tumour cells, or tumour-associated interstitial or immune cells. These may then act directly on muscle to cause atrophy and/or may cause anorexia, which then leads to loss of both fat and lean mass. Although the aetiological triggers for this syndrome are not well characterized, recent data suggest that MIC-1/GDF15, a transforming growth factor-beta superfamily cytokine produced in large amounts by cancer cells and as a part of other disease processes, may be an important trigger. This cytokine acts on feeding centres in the hypothalamus and brainstem to cause anorexia leading to loss of lean and fat mass and eventually cachexia. In animal studies, the circulating concentrations of MIC-1/GDF15 required to cause this syndrome are similar to those seen in patients with advanced cancer, and at least some epidemiological studies support an association between MIC-1/GDF15 serum levels and measures of nutrition. This article will discuss its mechanisms of central appetite regulation, and the available data linking this action to anorexia-cachexia syndromes that suggest it is a potential target for therapy of cancer anorexia-cachexia and conversely may also be useful for the treatment of severe obesity.

Effects of high-fructose diets on central appetite signaling and cognitive function.

The consumption of fructose has increased tremendously over the last five decades, which is to a large extent due to the development of high-fructose corn syrup (HFCS), a commercial sugar additive that contains high amounts of free fructose. HFCS is often added to processed food and beverages partly because it is a powerful sweetener but even more so because the production is cheap. Although fructose in combination with fiber, vitamins, and minerals, as present in fruits, is a healthy source of energy, isolated fructose, in processed food products has been associated with several health disorders such as insulin resistance and hypertension. Apart from its metabolic consequences, a growing body of literature suggests that free fructose can also affect neuronal systems. High-fructose intake may on the one hand affect central appetite regulation by altering specific components of the endocannabinoid system. On the other hand, it appears to impact on cognitive function by affecting phosphorylation levels of insulin receptor, synapsin 1, and synaptophysin. The present report reviews the recent evidence showing a negative effect of free fructose consumption on central appetite control, as well as cognitive function.

Serine-727 phosphorylation activates hypothalamic STAT-3 independently from tyrosine-705 phosphorylation.

Transcriptional activity of signal transducer and activator of transcription-3 (STAT-3) is a key element in the central regulation of appetite and energy homeostasis. Activation of hypothalamic STAT-3 has been attributed to cytokine-promoted phosphorylation at tyrosine-705 (Tyr-705). In nonhypothalamic cells, STAT-3 is also phosphorylated at serine-727 (Ser-727), but the functional significance of Ser-727 in the regulation of hypothalamic STAT-3 is not known. We used 2 hypothalamic cell lines and analyzed the effects of various hormones on STAT-3-dependent reporter gene activity and observed that IFN-γ, epidermal growth factor (EGF), and bradykinin (BK) induce similar STAT-3 reporter activation. EGF and BK solely increased Ser-727 and IFN-γ increased Tyr-705 phosphorylation of STAT-3. Specific inhibition of ERK-1/2 activity blocked EGF- and BK-induced STAT-3 activation and Ser-727 phosphorylation. BK-induced ERK-1/2 activation occurred via EGF receptor transactivation. Consequently, the BK-mediated effects on STAT-3 were blocked by a specific EGF receptor antagonist. Next, we analyzed the effects of IFN-γ and EGF on the expression of the STAT-3-dependent genes thyroliberin-releasing hormone and suppressors of cytokine signaling-3. EGF but not IFN-γ enhanced thyroliberin-releasing hormone expression via STAT-3. With regard to suppressors of cytokine signaling-3, we observed prolonged expression induced by IFN-γ and a transient effect of EGF that required coactivation of the activator protein-1. Thus, EGF-promoted Ser-727 phosphorylation by ERK-1/2 is not only sufficient to fully activate hypothalamic STAT-3, but, in terms of targeted genes and required cofactors, entails distinct modes of STAT-3 actions compared with IFN-γ-induced Tyr-705 phosphorylation.

Control of appetite and energy intake by SCFA: what are the potential underlying mechanisms?

In recent years, there has been a renewed interest in the role of dietary fibre in obesity management. Much of this interest stems from animal and human studies which suggest that an increased intake of fermentable fibre can suppress appetite and improve weight management. A growing number of reports have demonstrated that the principal products of colonic fermentation of dietary fibre, SCFA, contribute to energy homeostasis via effects on multiple cellular metabolic pathways and receptor-mediated mechanisms. In particular, over the past decade it has been identified that a widespread receptor system exists for SCFA. These G-protein-coupled receptors, free fatty acid receptor (FFAR) 2 and FFAR3 are expressed in numerous tissue sites, including the gut epithelium and adipose tissue. Investigations using FFAR2- or FFAR3-deficient animal models suggest that SCFA-mediated stimulation of these receptors enhances the release of the anorectic hormones peptide tyrosine tyrosine and glucagon-like peptide-1 from colonic L cells and leptin from adipocytes. In addition, the SCFA acetate has recently been shown to have a direct role in central appetite regulation. Furthermore, the SCFA propionate is a known precursor for hepatic glucose production, which has been reported to suppress feeding behaviour in ruminant studies through the stimulation of hepatic vagal afferents. The present review therefore proposes that an elevated colonic production of SCFA could stimulate numerous hormonal and neural signals at different organ and tissue sites that would cumulatively suppress short-term appetite and energy intake.

The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism.

Increased intake of dietary carbohydrate that is fermented in the colon by the microbiota has been reported to decrease body weight, although the mechanism remains unclear. Here we use in vivo11C-acetate and PET-CT scanning to show that colonic acetate crosses the blood–brain barrier and is taken up by the brain. Intraperitoneal acetate results in appetite suppression and hypothalamic neuronal activation patterning. We also show that acetate administration is associated with activation of acetyl-CoA carboxylase and changes in the expression profiles of regulatory neuropeptides that favour appetite suppression. Furthermore, we demonstrate through 13C high-resolution magic-angle-spinning that 13C acetate from fermentation of 13C-labelled carbohydrate in the colon increases hypothalamic 13C acetate above baseline levels. Hypothalamic 13C acetate regionally increases the 13C labelling of the glutamate–glutamine and GABA neuroglial cycles, with hypothalamic 13C lactate reaching higher levels than the ‘remaining brain’. These observations suggest that acetate has a direct role in central appetite regulation.