Seeking satiety: From signals to solutions.

Remedies for the treatment of obesity date to Hippocrates, when patients with obesity were directed to "reduce food and avoid drinking to fullness" and begin "running during the night." Similar recommendations have been repeated ever since, despite the fact that they are largely ineffective. Recently, highly effective therapeutics were developed that may soon enable physicians to manage body weight in patients with obesity in a manner similar to the way that blood pressure is controlled in patients with hypertension. These medicines have grown out of a revolution in our understanding of the molecular and neural control of appetite and body weight, reviewed here.

Secretin modulates appetite via brown adipose tissue-brain axis.

PURPOSE: Secretin activates brown adipose tissue (BAT) and induces satiation in both mice and humans. However, the exact brain mechanism of this satiety inducing, secretin-mediated gut-BAT-brain axis is largely unknown. METHODS AND RESULTS: In this placebo-controlled, single-blinded neuroimaging study, firstly using [18F]-fluorodeoxyglucose (FDG) PET measures (n = 15), we established that secretin modulated brain glucose consumption through the BAT-brain axis. Predominantly, we found that BAT and caudate glucose uptake levels were negatively correlated (r = -0.54, p = 0.037) during secretin but not placebo condition. Then, using functional magnetic resonance imaging (fMRI; n = 14), we found that secretin improved inhibitory control and downregulated the brain response to appetizing food images. Finally, in a PET-fMRI fusion analysis (n = 10), we disclosed the patterned correspondence between caudate glucose uptake and neuroactivity to reward and inhibition, showing that the secretin-induced neurometabolic coupling patterns promoted satiation. CONCLUSION: These findings suggest that secretin may modulate the BAT-brain metabolic crosstalk and subsequently the neurometabolic coupling to induce satiation. The study advances our understanding of the secretin signaling in motivated eating behavior and highlights the potential role of secretin in treating eating disorders and obesity. TRIAL REGISTRATION: EudraCT no. 2016-002373-35, registered 2 June 2016; Clinical Trials no. NCT03290846, registered 25 September 2017.

Influence of exclusive breastfeeding on hippocampal structure, satiety responsiveness, and weight status.

Longer exclusive breastfeeding duration has been associated with differences in neural development, better satiety responsiveness, and decreased risk for childhood obesity. Given hippocampus sensitivity to diet and potential role in the integration of satiety signals, hippocampus may play a role in these relationships. We conducted a secondary analysis of 149, 7-11-year-olds (73 males) who participated in one of five studies that assessed neural responses to food cues. Hippocampal grey matter volume was extracted from structural scans using CAT12, weight status was assessed using age- and sex-adjusted body mass index (%BMIp85 ), and parents reported exclusive breastfeeding duration and satiety responsiveness (Children's Eating Behaviour Questionnaire). Separate path models for left and right hippocampus tested: (1) the direct effect of exclusive breastfeeding on satiety responsiveness and its indirect effect through hippocampal grey matter volume; (2) the direct effect of hippocampal grey matter volume on %BMIp85 and its indirect effect through satiety responsiveness. %BMIp85 was adjusted for maternal education, yearly income, and premature birth while hippocampal grey matter volume was adjusted for total intercranial volume, age, and study from which data were extracted. Longer exclusive breastfeeding duration was associated with greater bilateral hippocampal grey matter volumes. In addition, better satiety responsiveness and greater left hippocampal grey matter volume were both associated with lower %BMIp85 . However, hippocampal grey matter volumes were not associated with satiety responsiveness. Although no relationship was found between breastfeeding and child weight status, these results highlight the potential impact of exclusive breastfeeding duration on the hippocampal structure.

Impact of food processing on postprandial glycaemic and appetite responses in healthy adults: a randomized, controlled trial.

Chickpeas are among the lowest glycaemic index carbohydrate foods eliciting protracted digestion and enhanced satiety responses. In vitro studies suggest that mechanical processing of chickpeas significantly increases starch digestion. However, there is little evidence regarding the impact of processing on postprandial glycaemic response in response to chickpea intake in vivo. Therefore, the aim of this study was to determine the effect of mechanical processing on postprandial interstitial glycaemic and satiety responses in humans. In a randomised crossover design, thirteen normoglycaemic adults attended 4 separate laboratory visits following an overnight fast. On each occasion, one of four test meals, matched for available carbohydrate content and consisting of different physical forms of chickpeas (whole, puree, and pasta) or control (mashed potato), was administered followed by a subsequent standardised lunch meal. Continuous glucose monitoring captured interstitial glucose responses, accompanied by periodic venous blood samples for retrospective analysis of C-peptide, glucagon like peptide-1 (GLP-1), ghrelin, leptin, resistin, and cortisol. Subjective appetite responses were measured by Visual Analogue Scale (VAS). Postprandial glycaemic responses were comparable between chickpea treatments albeit significantly lower than the control (p < 0.001). Similarly, all chickpea treatments elicited significantly lower C-peptide and GLP-1 responses compared to the control (p < 0.05), accompanied by enhanced subjective satiety responses (p < 0.05), whilst no significant differences in satiety hormones were detected among different intervention groups (p > 0.05). Chickpea consumption elicits low postprandial glycaemic responses and enhanced subjective satiety responses irrespective of processing methods.

Glycaemic and Appetite Suppression Effect of a Vegetable-Enriched Bread.

Bread, a frequently consumed food, is an ideal vehicle for addition of ingredients that increase nutrient density and add health benefits. This experimental cross-over study sought to test the effect of a vegetable-enriched bread (VB) in comparison to commercial white bread (WB) and wheatmeal bread (WMB) on serum glucose, insulin response and subjective appetite suppression. On three separate occasions, 10 participants (23 ± 7 years) visited the laboratory and consumed after an overnight fast, in random order, a 75 g serve of WB, WMB or VB. Venous blood samples drawn twice before (0 min) and at 15, 30, 45, 60, 90 and 120 min after consumption of the bread were analysed for glucose and insulin. Participants rated their subjective feelings of hunger, fullness, satisfaction and desire to eat on a 150 mm Likert scale. The mean glucose iAUC over 120 min was not different among the breads. The mean insulin iAUC for the VB was significantly lower than the WB and WMB; difference VB and WB 12,415 pmol/L*minutes (95% CI 1918, 22,912 pmol/L*minutes, p = 0.025) and difference VB and WMB 13,800 pmol/L*minutes (95% CI 1623, 25,976 pmol/L*minutes p = 0.031). The VB was associated with a higher fullness feeling in the participants over the 120-min period. The consumption of VB was associated with less insulin release and higher satiety over 120 min which may be related to the higher fibre content and texture of VB. The role of vegetable and fruit fibres such as pectin in bread and insulin response should also be further explored.

Reverse-translational identification of a cerebellar satiation network.

The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1-3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically -distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a 'bedside-to-bench' approach for the identification of neural circuits that influence behaviour.

Associations between ghrelin and leptin and neural food cue reactivity in a fasted and sated state.

Food cue exposure can trigger eating. Food cue reactivity (FCR) is a conditioned response to food cues and includes physiological responses and activation of reward-related brain areas. FCR can be affected by hunger and weight status. The appetite-regulating hormones ghrelin and leptin play a pivotal role in homeostatic as well as hedonic eating. We examined the association between ghrelin and leptin levels and neural FCR in the fasted and sated state and the association between meal-induced changes in ghrelin and neural FCR, and in how far these associations are related to BMI and HOMA-IR. Data from 109 participants from three European centers (age 50±18 y, BMI 27±5 kg/m2) who performed a food viewing task during fMRI after an overnight fast and after a standardized meal were analyzed. Blood samples were drawn prior to the viewing task in which high-caloric, low-caloric and non-food images were shown. Fasting ghrelin was positively associated with neural FCR in the inferior and superior occipital gyrus in the fasted state. This was partly attributable to BMI and HOMA-IR. These brain regions are involved in visual attention, suggesting that individuals with higher fasting ghrelin have heightened attention to food cues. Leptin was positively associated with high calorie FCR in the medial prefrontal cortex (PFC) in the fasted state and to neural FCR in the left supramarginal gyrus in the fasted versus sated state, when correcting for BMI and HOMA-IR, respectively. This PFC region is involved in assessing anticipated reward value, suggesting that for individuals with higher leptin levels high-caloric foods are more salient than low-caloric foods, but foods in general are not more salient than non-foods. There were no associations between ghrelin and leptin and neural FCR in the sated state, nor between meal-induced changes in ghrelin and neural FCR. In conclusion, we show modest associations between ghrelin and leptin and neural FCR in a relatively large sample of European adults with a broad age and BMI range. Our findings indicate that people with higher leptin levels for their weight status and people with higher ghrelin levels may be more attracted to high caloric foods when hungry. The results of the present study form a foundation for future studies to test whether food intake and (changes in) weight status can be predicted by the association between (mainly fasting) ghrelin and leptin levels and neural FCR.

Reward-specific satiety affects subjective value signals in orbitofrontal cortex during multicomponent economic choice.

Sensitivity to satiety constitutes a basic requirement for neuronal coding of subjective reward value. Satiety from natural ongoing consumption affects reward functions in learning and approach behavior. More specifically, satiety reduces the subjective economic value of individual rewards during choice between options that typically contain multiple reward components. The unconfounded assessment of economic reward value requires tests at choice indifference between two options, which is difficult to achieve with sated rewards. By conceptualizing choices between options with multiple reward components ("bundles"), Revealed Preference Theory may offer a solution. Despite satiety, choices against an unaltered reference bundle may remain indifferent when the reduced value of a sated bundle reward is compensated by larger amounts of an unsated reward of the same bundle, and then the value loss of the sated reward is indicated by the amount of the added unsated reward. Here, we show psychophysically titrated choice indifference in monkeys between bundles of differently sated rewards. Neuronal chosen value signals in the orbitofrontal cortex (OFC) followed closely the subjective value change within recording periods of individual neurons. A neuronal classifier distinguishing the bundles and predicting choice substantiated the subjective value change. The choice between conventional single rewards confirmed the neuronal changes seen with two-reward bundles. Thus, reward-specific satiety reduces subjective reward value signals in OFC. With satiety being an important factor of subjective reward value, these results extend the notion of subjective economic reward value coding in OFC neurons.

Leptin and Obesity: Role and Clinical Implication.

The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a product of the obese (ob) gene and, following synthesis and secretion from fat cells in white adipose tissue, binds to and activates its cognate receptor, the leptin receptor (LEP-R). LEP-R distribution facilitates leptin's pleiotropic effects, playing a crucial role in regulating body mass via a negative feedback mechanism between adipose tissue and the hypothalamus. Leptin resistance is characterized by reduced satiety, over-consumption of nutrients, and increased total body mass. Often this leads to obesity, which reduces the effectiveness of using exogenous leptin as a therapeutic agent. Thus, combining leptin therapies with leptin sensitizers may help overcome such resistance and, consequently, obesity. This review examines recent data obtained from human and animal studies related to leptin, its role in obesity, and its usefulness in obesity treatment.

Impact of a prenatal education intervention in pregnant women to prevent overweight in infants.

INTRODUCTION: During the first 1000 days of life is the basis for a child's future health established. OBJECTIVE: To evaluate the impact of a prenatal educational intervention in pregnant women on the nutritional status of the child from birth to 4 months of age. METHODS: Quasi-experimental intervention design in women with at least 12 weeks of gestation, who were randomly assigned to an intervention group (IG) to participate in five group and three individual sessions on feeding practices and maternal perception of the child's weight and signals of hunger-satiety; the control group (CG) received routine care that included at least three prenatal consultations. RESULTS: Thirty women were included in each group. After the intervention, women in the CG practiced less exclusive breastfeeding, were more likely to underestimate or overestimate the children's weight, and perceived hunger-satiety signals with less intensity (p < 0.05). 80 % of the infants in the IG had normal weight, whereas 63 % of those in the CG had a combination of overweight and obesity (p < 0.05). CONCLUSIONS: The prenatal education program in pregnant women showed a significant effect on postnatal nutritional status of infants four months after birth.

INTRODUCCIÓN: Durante los primeros 1000 días de vida se establece la base para la salud futura de un niño. OBJETIVO: Evaluar el impacto de una intervención educativa prenatal en mujeres embarazadas sobre el estado nutricional del hijo desde el nacimiento hasta los cuatro meses de edad. MÉTODOS: Diseño cuasiexperimental de intervención con mujeres a partir de la semana 12 de gestación, asignadas aleatoriamente a un grupo de intervención (GI) para recibir cinco sesiones grupales y tres individuales sobre prácticas de alimentación y percepción materna del peso del hijo y de señales de hambre-saciedad; el grupo control (GC) recibió atención de rutina que incluía al menos tres consultas prenatales. RESULTADOS: 30 mujeres conformaron cada grupo. Después de la intervención, las mujeres del GC practicaron menos lactancia materna exclusiva, fueron propensas a subestimar o sobrestimar el peso del hijo y percibieron con menor intensidad las señales de hambre-saciedad (p < 0.05). El 80 % de los lactantes del GI presentaron peso normal y 63 % de los niños del GC, una combinación de sobrepeso y obesidad (p < 0.05). CONCLUSIONES: El programa de educación prenatal en mujeres embarazadas mostró un efecto significativo en el estado nutricional de los lactantes después de cuatro meses del nacimiento.

Periphery signals generated by Piezo-mediated stomach stretch and Neuromedin-mediated glucose load regulate the Drosophila brain nutrient sensor.

Nutrient sensors allow animals to identify foods rich in specific nutrients. The Drosophila nutrient sensor, diuretic hormone 44 (DH44) neurons, helps the fly to detect nutritive sugar. This sensor becomes operational during starvation; however, the mechanisms by which DH44 neurons or other nutrient sensors are regulated remain unclear. Here, we identified two satiety signals that inhibit DH44 neurons: (1) Piezo-mediated stomach/crop stretch after food ingestion and (2) Neuromedin/Hugin neurosecretory neurons in the ventral nerve cord (VNC) activated by an increase in the internal glucose level. A subset of Piezo+ neurons that express DH44 neuropeptide project to the crop. We found that DH44 neuronal activity and food intake were stimulated following a knockdown of piezo in DH44 neurons or silencing of Hugin neurons in the VNC, even in fed flies. Together, we propose that these two qualitatively distinct peripheral signals work in concert to regulate the DH44 nutrient sensor during the fed state.

Vagally Mediated Gut-Brain Relationships in Appetite Control-Insights from Porcine Studies.

Signals arising from the upper part of the gut are essential for the regulation of food intake, particularly satiation. This information is supplied to the brain partly by vagal nervous afferents. The porcine model, because of its sizeable gyrencephalic brain, omnivorous regimen, and comparative anatomy of the proximal part of the gut to that of humans, has provided several important insights relating to the relevance of vagally mediated gut-brain relationships to the regulation of food intake. Furthermore, its large size combined with the capacity to become obese while overeating a western diet makes it a pivotal addition to existing murine models, especially for translational studies relating to obesity. How gastric, proximal intestinal, and portal information relating to meal arrival and transit are encoded by vagal afferents and their further processing by primary and secondary brain projections are reviewed. Their peripheral and central plasticities in the context of obesity are emphasized. We also present recent insights derived from chronic stimulation of the abdominal vagi with specific reference to the modulation of mesolimbic structures and their role in the restoration of insulin sensitivity in the obese miniature pig model.

Central and peripheral GLP-1 systems independently suppress eating.

The anorexigenic peptide glucagon-like peptide-1 (GLP-1) is secreted from gut enteroendocrine cells and brain preproglucagon (PPG) neurons, which, respectively, define the peripheral and central GLP-1 systems. PPG neurons in the nucleus tractus solitarii (NTS) are widely assumed to link the peripheral and central GLP-1 systems in a unified gut-brain satiation circuit. However, direct evidence for this hypothesis is lacking, and the necessary circuitry remains to be demonstrated. Here we show that PPGNTS neurons encode satiation in mice, consistent with vagal signalling of gastrointestinal distension. However, PPGNTS neurons predominantly receive vagal input from oxytocin-receptor-expressing vagal neurons, rather than those expressing GLP-1 receptors. PPGNTS neurons are not necessary for eating suppression by GLP-1 receptor agonists, and concurrent PPGNTS neuron activation suppresses eating more potently than semaglutide alone. We conclude that central and peripheral GLP-1 systems suppress eating via independent gut-brain circuits, providing a rationale for pharmacological activation of PPGNTS neurons in combination with GLP-1 receptor agonists as an obesity treatment strategy.

Impacto de una intervención de educación prenatal en mujeres embarazadas para prevenir el sobrepeso en lactantes / Impact of a prenatal education intervention in pregnant women to prevent overweight in infants

Resumen Introducción: Durante los primeros 1000 días de vida se establece la base para la salud futura de un niño. Objetivo: Evaluar el impacto de una intervención educativa prenatal en mujeres embarazadas sobre el estado nutricional del hijo desde el nacimiento hasta los cuatro meses de edad. Métodos: Diseño cuasiexperimental de intervención con mujeres a partir de la semana 12 de gestación, asignadas aleatoriamente a un grupo de intervención (GI) para recibir cinco sesiones grupales y tres individuales sobre prácticas de alimentación y percepción materna del peso del hijo y de señales de hambre-saciedad; el grupo control (GC) recibió atención de rutina que incluía al menos tres consultas prenatales. Resultados: 30 mujeres conformaron cada grupo. Después de la intervención, las mujeres del GC practicaron menos lactancia materna exclusiva, fueron propensas a subestimar o sobrestimar el peso del hijo y percibieron con menor intensidad las señales de hambre-saciedad (p < 0.05). El 80 % de los lactantes del GI presentaron peso normal y 63 % de los niños del GC, una combinación de sobrepeso y obesidad (p < 0.05). Conclusiones: El programa de educación prenatal en mujeres embarazadas mostró un efecto significativo en el estado nutricional de los lactantes después de cuatro meses del nacimiento.

Abstract Introduction: During the first 1000 days of life is the basis for a child‘s future health established. Objective: To evaluate the impact of a prenatal educational intervention in pregnant women on the nutritional status of the child from birth to 4 months of age. Methods: Quasi-experimental intervention design in women with at least 12 weeks of gestation, who were randomly assigned to an intervention group (IG) to participate in five group and three individual sessions on feeding practices and maternal perception of the child’s weight and signals of hunger-satiety; the control group (CG) received routine care that included at least three prenatal consultations. Results: Thirty women were included in each group. After the intervention, women in the CG practiced less exclusive breastfeeding, were more likely to underestimate and overestimate the children’s weight, and perceived hunger-satiety signals with less intensity (p < 0.05). 80 % of the infants in the IG had normal weight, whereas 63 % of those in the CG had a combination of overweight and obesity (p < 0.05). Conclusions: The prenatal education program in pregnant women showed a significant effect on postnatal nutritional status of infants four months after birth.

Changes in Ghrelin and Glucagon following a Low Glycemic Load Diet in Women with PCOS.

CONTEXT: Altered satiety hormones in women with polycystic ovarian syndrome (PCOS) may contribute to obesity. Diets with a low glycemic load (GL) may influence appetite-regulating hormones including glucagon and ghrelin. OBJECTIVE: To test the hypothesis that following a 4-week, eucaloric low vs high GL diet habituation, a low vs high GL meal will increase glucagon and decrease ghrelin to reflect greater satiety and improve self-reported fullness. METHODS: Secondary analysis of a randomized crossover trial. PARTICIPANTS: Thirty women diagnosed with PCOS. INTERVENTION: Participants were provided low (41:19:40% energy from carbohydrate:protein:fat) and high (55:18:27) GL diets for 8 weeks each. At each diet midpoint, a solid meal test was administered to examine postprandial ghrelin, glucagon, glucose, insulin, and self-reported appetite scores. RESULTS: After 4 weeks, fasting glucagon was greater with the low vs high GL diet (P = .035), and higher fasting glucagon was associated with lesser feelings of hunger (P = .009). Significant diet effects indicate 4-hour glucagon was higher (P < .001) and ghrelin was lower (P = .009) after the low vs high GL meal. A trending time × diet interaction (P = .077) indicates feelings of fullness were greater in the early postprandial phase after the high GL meal, but no differences were observed the late postprandial phase. CONCLUSION: These findings suggest after low GL diet habituation, a low GL meal reduces ghrelin and increases glucagon in women with PCOS. Further research is needed to determine the influence of diet composition on ad libitum intake in women with PCOS.

A Pilot Study of Gut-Brain Signaling After Octreotide Therapy for Unintentional Weight Loss After Esophagectomy.

BACKGROUND: Recurrence-free patients after esophageal cancer surgery face long-term nutritional consequences, occurring in the context of an exaggerated postprandial gut hormone response. Acute gut hormone suppression influences brain reward signaling and eating behavior. This study aimed to suppress gut hormone secretion and characterize reward responses and eating behavior among postesophagectomy patients with unintentional weight loss. METHODS: This pilot study prospectively studied postoperative patients with 10% or greater body weight loss (BWL) beyond 1 year who were candidates for clinical treatment with long-acting octreotide (LAR). Before and after 4 weeks of treatment, gut hormone secretion, food cue reactivity (functional magnetic resonance imaging), eating motivation (progressive ratio task), ad libitum food intake, body composition, and symptom burden were assessed. RESULTS: Eight patients (7 male, age: mean ±â€…SD 62.8 ±â€…9.4 years, postoperative BWL: 15.5 ±â€…5.8%) participated. Octreotide LAR did not significantly suppress total postprandial plasma glucagon-like peptide-1 response at 4 weeks (P = .08). Postprandial symptom burden improved after treatment (Sigstad score median [range]: 12 [2-28] vs 8 [3-18], P = .04) but weight remained stable (pre: 68.6 ±â€…12.8 kg vs post: 69.2 ±â€…13.4 kg, P = .13). There was no significant change in brain reward system responses, during evaluation of high-energy or low-energy food pictures, nor their appeal rating. Moreover, treatment did not alter motivation to eat (P = .41) nor ad libitum food intake(P = .46). CONCLUSION: The protocol used made it feasible to characterize the gut-brain axis and eating behavior in this cohort. Inadequate suppression of gut hormone responses 4 weeks after octreotide LAR administration may explain the lack of gut-brain pathway alterations. A higher dose or shorter interdose interval may be required to optimize the intervention.

Effect of White Potatoes on Subjective Appetite, Food Intake, and Glycemic Response in Healthy Older Adults.

The objective of this study was to determine the effect of white potato cooking methods on subjective appetite, short-term food intake (FI), and glycemic response in healthy older adults. Using a within-subject, repeated-measures design, 20 participants (age: 70.4 ± 0.6 y) completed, in random order, five treatment conditions: three potato treatments (baked potatoes, mashed potatoes, and French fries), an isocaloric control treatment (white bread), or a fasting condition (meal skipping). Subjective appetite and glycemic response were measured for 120 min using visual analogue scales and capillary blood samples, respectively. Lunch FI was measured with an ad libitum pizza meal at 120 min. Change from baseline subjective appetite (p < 0.001) and lunch FI (p < 0.001) were lower after all test treatments compared with meal skipping (p < 0.001), but did not differ among test treatments. Cumulative FI (test treatment + lunch FI) did not differ among treatment conditions. Blood glucose concentrations were higher after all test treatments compared with meal skipping (p < 0.001), but were not different from each other. In healthy older adults, white potatoes suppressed subjective appetite and lunch FI compared with meal skipping, suggesting white potatoes do not bypass regulatory control mechanisms of FI.

Estrogen and gut satiety hormones in vagus-hindbrain axis.

Estrogens modulate different physiological functions, including reproduction, inflammation, bone formation, energy expenditure, and food intake. In this review, we highlight the effect of estrogens on food intake regulation and the latest literature on intracellular estrogen signaling. In addition, gut satiety hormones, such as cholecystokinin, glucagon-like peptide 1 and leptin are essential to regulate ingestive behaviors in the postprandial period. These peripheral signals are sensed by vagal afferent terminals in the gut wall and transmitted to the hindbrain axis. Here we 1. review the role of the vagus-hindbrain axis in response to gut satiety signals and 2. consider the potential synergistic effects of estrogens on gut satiety signals at the level of vagal afferent neurons and nuclei located in the hindbrain. Understanding the action of estrogens in gut-brain axis provides a potential strategy to develop estrogen-based therapies for metabolic diseases and emphasizes the importance of sex difference in the treatment of obesity.

Satiety induced by bile acids is mediated via vagal afferent pathways.

The aim of this study was to elucidate the role and the pathways used by bile acid receptor TGR5 in transmitting satiety signals. We showed TGR5 colocalized with cholecystokinin type A (CCK-A) receptors in a subpopulation of rat nodose ganglia (NG) neurons. Intra-arterial injection of deoxycholic acid (DCA) dose-dependently increased firing rate in NG while a subthreshold dose of DCA and CCK-8 increased firing rates synergistically. TGR5-specific agonist oleanolic acid induced NG neuronal firing in a dose-dependent manner. However, the same units did not respond to GW4064, a nuclear receptor-specific agonist. Quantity of DCA-activated neurons in the hypothalamus was determined by c-Fos expression. Combining DCA and CCK-8 caused a 4-fold increase in c-Fos activation. In the arcuate nucleus, c-Fos-positive neurons coexpressed cocaine and amphetamine regulated transcript and proopiomelanocortin. DCA-induced c-Fos expression was eliminated following truncal vagotomy or silencing of TGR5 in the NG. Feeding studies showed intravenous injection of 1 µg/kg of DCA reduced food intake by 12% ± 3%, 24% ± 5%, and 32% ± 6% in the first 3 hours, respectively. Silencing of TGR5 or CCK-A receptor in the NG enhanced spontaneous feeding by 18% ± 2% and 13.5% ± 2.4%, respectively. When both TGR5 and CCK-A receptor were silenced, spontaneous feeding was enhanced by 37% ± 4% in the first 3 hours, suggesting that bile acid may have a physiological role in regulating satiety. Working in concert with CCK, bile acid synergistically enhanced satiety signals to reduce spontaneous feeding.