Satiety Signals Research Articles

Dietary Habits, Obesity, and Bariatric Surgery: A Review of Impact and Interventions

Eating behavior encompasses the psychological, physiological, and environmental factors influencing food intake. Dysregulation in eating behavior, such as emotional eating, binge eating, or loss of satiety signals, contributes to excessive caloric intake and weight gain. These behaviors are often linked to hormonal imbalances, stress, or genetic predisposition. Obesity is a chronic, multifactorial disease characterized by excessive body fat accumulation, with a body mass index (BMI) ≥ 30 kg/m2 often used for diagnosis. It is associated with significant morbidity, including type 2 diabetes, cardiovascular disease, and obstructive sleep apnea. Pathophysiological mechanisms underlying obesity include insulin resistance, leptin dysregulation, and altered gut microbiota, which perpetuate metabolic derangements. Lifestyle interventions remain first-line treatment, but sustained weight loss is challenging for many patients. Bariatric surgery is a therapeutic option for individuals with severe obesity (BMI ≥ 40 kg/m2 or ≥35 kg/m2 with comorbidities) who have failed conservative management. Procedures such as Roux-en-Y gastric bypass and sleeve gastrectomy alter gastrointestinal anatomy, promoting weight loss through restriction, malabsorption, and hormonal modulation (e.g., increased GLP-1 secretion). Bariatric surgery improves obesity-related comorbidities and enhances quality of life. However, it requires lifelong medical follow-up to address potential nutritional deficiencies and ensure sustainable outcomes.

Appetite Self-Regulation in Childhood: A Narrative Review and Conceptual Model of Processes and Mechanisms With Implications for Research and Practice.

The purpose of the present narrative review was to propose a unifying generalized conceptual model of mechanisms and processes in appetite self-regulation (ASR) in childhood. Appetite self-regulation, along with other domains of self-regulation, develops across childhood and contributes to energy intake and balance, diet quality, weight, and therefore long-term health outcomes. There have been efforts to conceptualize and measure components of ASR and associated processes/mechanisms, but, at present, there is no unifying conceptualization of ASR in childhood. A search of key databases supplemented by snowballing was undertaken for definitions/conceptions and theoretical models of ASR with a focus on children. An interpretive synthesis approach was used to identify themes from the definitions and models. The themes formed the basis of the proposed unifying generalized model of ASR in childhood, which is the main contribution of the article. At the center of the model is bottom-up reactivity to food, food cues and hunger, satiation and satiety signals, together with top-down regulatory control. An additional contribution is the proposed 5 interacting and overlapping domains (biological, hedonics, cognitive, behavioral, and traits) that function in and influence both bottom-up reactivity and top-down regulation. The domains also contribute to ASR outcomes of enactment and competence. External contextual and intrapersonal factors are conceived as impacting the domains and the bottom-up, top-down processes. The relevance of the model for explanations of ASR phenomena in childhood and children's food choice and diet quality, as well as its implications for research directions and approaches to preventive intervention, including food parenting practices, are discussed. The model provides a framework for researchers and practitioners to support and interpret children's problems and competence in self-directing food choices, energy intake, and nutrition.

Characterizing brainstem glucagon-like peptide-1 control of sensory-specific-satiety in male and female rats across the estrous cycle.

Meal variety promotes overconsumption by delaying sensory-specific-satiety (SSS), the transient reduction in reward value of a recently consumed food. Despite its role in meal cessation, the neuroendocrine mechanisms underlying SSS are largely unknown. Here, we developed a preclinical model of SSS wherein rats consume more of a different food compared to the same food presented again, leading to greater caloric intake. Using pharmacological and molecular approaches targeting the brainstem, we investigated the involvement of the satiation signal, glucagon-like peptide-1 (GLP-1), in mediating SSS in male rats (n=96) and in female rats (n=85) across their estrous cycle. We also evaluated the sufficiency of the hormone estradiol to modulate GLP-1 and SSS. In males, brainstem GLP-1 receptors (GLP-1Rs) were necessary for the SSS-induced decrease in same food intake, while agonizing brainstem GLP-1Rs was sufficient to attenuate overconsumption of the different food. Female rats showed SSS in an estrous cycle-dependent manner and did not consume more of the different food in diestrus-to-Proestrus and proestrus-to-Estrus. However, blockade of brainstem GLP-1R restored different food overconsumption. Furthermore, the brainstem's nucleus tractus solitarius and area postrema showed increased expression of the GLP-1 precursor, glucagon (Gcg), during diestrus-to-Proestrus and proestrus-to-Estrus, and greater Glp1r expression in proestrus-to-Estrus. Similarly, 17β-estradiol injections in males not only increased Glp1r and Gcg expression, but also reduced SSS. We identified a bidirectional role for brainstem GLP-1R signaling in modulating SSS; effects that are estrous cycle-dependent. Moreover, our data indicate that estradiol regulates Glp1r and Gcg expression and likely influences SSS.

The microbiome's influence on obesity: mechanisms and therapeutic potential.

In 2023, the World Obesity Atlas Federation concluded that more than 50% of the world's population would be overweight or obese within the next 12 years. At the heart of this epidemic lies the gut microbiota, a complex ecosystem that profoundly influences obesity-related metabolic health. Its multifaced role encompasses energy harvesting, inflammation, satiety signaling, gut barrier function, gut-brain communication, and adipose tissue homeostasis. Recognizing the complexities of the cross-talk between host physiology and gut microbiota is crucial for developing cutting-edge, microbiome-targeted therapies to address the global obesity crisis and its alarming health and economic repercussions. This narrative review analyzed the current state of knowledge, illuminating emerging research areas and their implications for leveraging gut microbial manipulations as therapeutic strategies to prevent and treat obesity and related disorders in humans. By elucidating the complex relationship between gut microflora and obesity, we aim to contribute to the growing body of knowledge underpinning this critical field, potentially paving the way for novel interventions to combat the worldwide obesity epidemic.

Oxytocin neurons in the paraventricular and supraoptic hypothalamic nuclei bidirectionally modulate food intake.

Oxytocin (OT) is a neuropeptide produced in the paraventricular (PVH) and supraoptic (SON) nuclei of the hypothalamus. Either peripheral or central administration of OT suppresses food intake through reductions in meal size. However, pharmacological approaches do not differentiate whether observed effects are mediated by OT neurons located in the PVH or in the SON. To address this, we targeted OT neuron-specific designer receptors exclusively activated by designer drugs (DREADDs) in either the PVH or SON in rats, thus allowing for evaluation of food intake following selective activation of OT neurons separately in each nucleus. Results revealed that DREADDs-mediated excitation of PVH OT neurons reduced consumption of both standard chow and a high fat high sugar diet (HFHS) via reductions in meal size. On the contrary, SON OT neuron activation had the opposite effect by increasing both standard chow and liquid sucrose consumption, with the former effect mediated by an increase in meal size. To further examine the physiological role of OT neurons in eating behavior, a viral-mediated approach was used to silence synaptic transmission of OT neurons separately in either the PVH or SON. Results from these studies revealed that PVH OT neuron silencing significantly increased consumption of HFHS by increasing meal size whereas SON OT neuron silencing reduced chow consumption by decreasing meal size. Collectively these data reveal that PVH and SON OT neurons differentially modulate food intake by either increasing or decreasing satiation signaling, respectively.

Reduced Liver Mitochondrial Energy Metabolism Impairs Food Intake Regulation Following Gastric Preloads and Fasting.

The capacity of the liver to serve as a peripheral sensor in the regulation of food intake has been debated for over half a century. The anatomical position and physiological roles of the liver suggest it is a prime candidate to serve as an interoceptive sensor of peripheral tissue and systemic energy state. Importantly, maintenance of liver ATP levels and within- meal food intake inhibition is impaired in human subjects with obesity and obese pre- clinical models. We demonstrate that decreased hepatic mitochondrial energy metabolism in liver-specific, heterozygous PGC1a mice results in reduced mitochondrial response to changes in ΔGATP and tissue ATP following fasting. These impairments in liver energy state are associated with larger and longer meals during chow feeding, impaired dose-dependent food intake inhibition in response to mixed and individual nutrient oral pre-loads, and greater acute fasting-induced food intake. These data support previous work proposing liver-mediated food intake regulation through modulation of peripheral satiation signals.

Proteins and Peptides from Food Sources with Effect on Satiety and Their Role as Anti-Obesity Agents: A Narrative Review.

Obesity, clinically defined as a body mass index (BMI) of 30 kg/m2 or higher, is a medical condition characterized by the excessive accumulation of body fat, which can lead to adverse health consequences. As a global public health issue with an escalating prevalence, controlling appetite and satiety is essential for regulating energy balance and managing body weight. Dietary proteins and peptides have gained interest in their potential to prevent and treat obesity by modulating satiety signals. This narrative review analyzes scientific evidence highlighting the role of dietary proteins and peptides in regulating satiety signals and investigates their therapeutic potential in preventing and treating obesity. A comprehensive literature search was conducted in multiple electronic databases, including PubMed, Scopus, and Web of Science. The search focused on articles examining the impact of dietary proteins and peptides on satiety and obesity, encompassing both preclinical and clinical trials. Several studies have demonstrated a correlation between the intake of specific proteins or peptides from plant and animal sources and satiety regulation. These investigations identified mechanisms where amino acids and peptides interact with enteroendocrine cell receptors, activating intracellular signaling cascades that promote the release of anorexigenic gut hormones such as cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY). Both in vitro and in vivo assays have shown that these interactions contribute to appetite regulation and the sensation of satiety. Using proteins and peptides in the diet may be an effective strategy for regulating appetite and controlling body weight. However, more research-including clinical trials-is needed to understand the underlying mechanisms better and optimize the application of these bioactive compounds in preventing and treating obesity.

The glucagon-like peptide-1 and other endocrine responses to alcohol ingestion in women with versus without metabolic surgery.

Glucagon-like peptide-1 (GLP-1)-based therapies, effective in treating obesity and type 2 diabetes, hold potential for reducing alcohol-seeking behaviour. However, the understanding of how alcohol consumption affects endogenous GLP-1 responses-important for understanding GLP-1-based therapies' potential in addressing alcohol misuse-is limited, given the absence of placebo-controlled studies examining these effects. This study aimed to determine the acute effects of alcohol ingestion on GLP-1 and other peptides and evaluate whether metabolic surgery, which increases GLP-1 responses, blood alcohol concentrations (BAC) and alcohol misuse risk, influences this effect. Additionally, we assessed the acute effects of alcohol on plasma glucose and insulin concentrations. Using a placebo-controlled crossover study, we examined hormonal and glucose responses after oral alcohol consumption (0.5g/kg of fat-free mass) versus placebo drinks in 18 women who underwent metabolic surgery <5years ago and in 14 non-operated controls (equivalent in age, body mass index [BMI], race and alcohol consumption patterns). Women had a mean (SD) age of 41 (10) years and a BMI of 33 (5) kg/m2. Compared with the control group, the surgery group exhibited a higher peak BAC (0.99 [0.20] g/L vs. 0.75 [0.16] g/L; P < 0.005). Alcohol decreased GLP-1 by 34% (95% CI, 16%-52%) in both groups and decreased ghrelin more in the control (27%) than in the surgery group (13%). Alcohol modestly decreased plasma glucose and transiently increased insulin secretion in both groups (P < 0.05). However, alcohol lowered blood glucose concentrations to the hypoglycaemic range in 28% of the women in the surgery group versus none in the control group. These findings provide compelling evidence that acute alcohol consumption decreases GLP-1, a satiation signal, elucidating alcohol's 'apéritif' effect. This study also highlights the potential increase in alcohol-related hypoglycaemic effects after metabolic surgery.

Associations of pre- and postnatal per- and polyfluoroalkyl substance exposure with adolescents' eating behaviors.

Per- and polyfluoroalkyl substances (PFAS), persistent environmental chemicals, may act as obesogens by interacting with neuroendocrine pathways regulating energy homeostasis and satiety signals influencing adolescent eating behaviors. In 211 HOME Study adolescents (Cincinnati, OH; recruited 2003-2006), we measured PFAS concentrations in serum collected during pregnancy, at delivery, and at ages 3, 8, and 12 years. Caregivers completed the Child Eating Behavior Questionnaire (CEBQ) at age 12, and we calculated food approach and food avoidance scores. Using quantile-based g-computation, we estimated covariate-adjusted associations between a mixture of four gestational PFAS and CEBQ scores. We identified high (n = 76, 36%) and low (n = 135, 64%) longitudinal PFAS mixture exposure profiles between delivery and age 12 years using latent profile analysis and related these to CEBQ scores. We examined whether child sex or physical activity modified these associations. We observed no association of gestational PFAS mixture with food approach or food avoidance scores. Children in the higher longitudinal PFAS mixture profile had slightly higher food approach scores (β: 0.47, 95% CI: -0.27, 1.23) and similar food avoidance scores (β: -0.15, 95% CI: -0.75, 0.46) compared with children in the lower profile. We found some evidence that higher physical activity favorably modified the association between longitudinal PFAS mixture profiles and emotional overeating (interaction P value = 0.13). Child sex did not consistently modify any associations. Serum PFAS concentrations were not consistently linked to adolescent eating behaviors in this study, suggesting alternative pathways, such as metabolic rate, may underlie previously observed associations between PFAS exposure and childhood obesity.

The Possible Involvement of Glucagon-like Peptide-2 in the Regulation of Food Intake through the Gut-Brain Axis.

Food intake regulation is a complex mechanism involving the interaction between central and peripheral structures. Among the latter, the gastrointestinal tract represents one of the main sources of both nervous and hormonal signals, which reach the central nervous system that integrates them and sends the resulting information downstream to effector organs involved in energy homeostasis. Gut hormones released by nutrient-sensing enteroendocrine cells can send signals to central structures involved in the regulation of food intake through more than one mechanism. One of these is through the modulation of gastric motor phenomena known to be a source of peripheral satiety signals. In the present review, our attention will be focused on the ability of the glucagon-like peptide 2 (GLP-2) hormone to modulate gastrointestinal motor activity and discuss how its effects could be related to peripheral satiety signals generated in the stomach and involved in the regulation of food intake through the gut-brain axis. A better understanding of the possible role of GLP-2 in regulating food intake through the gut-brain axis could represent a starting point for the development of new strategies to treat some pathological conditions, such as obesity.

Genes Involved in Susceptibility to Obesity and Emotional Eating Behavior in a Romanian Population.

Obesity, a significant public health concern with high prevalence in both adults and children, is a complex disorder arising from the interaction of multiple genes and environmental factors. Advances in genome-wide association studies (GWAS) and sequencing technologies have identified numerous polygenic causes of obesity, particularly genes involved in hunger, satiety signals, adipocyte differentiation, and energy expenditure. This study investigates the relationship between six obesity-related genes (CLOCK, FTO, GHRL, LEP, LEPR, MC4R) and their impact on BMI, WC, HC, WHR, and emotional eating behavior in 220 Romanian adults. Emotional eating was assessed using the validated Emotional Eating Questionnaire (EEQ). Our analysis revealed significant variability in obesity-related phenotypes and emotional eating behaviors across different genotypes. Specifically, CLOCK/CC, FTO/AA, and LEP/AA genotypes were strongly associated with higher obesity metrics and emotional eating scores, while GHRL/TT and MC4R/CC were linked to increased BMI and WHR. The interplay between genetic predisposition and emotional eating behavior significantly influenced BMI and WHR, indicating a complex relationship between genetic and behavioral factors. This study, the first of its kind in Romania, provides a foundation for targeted interventions to prevent and reduce obesity and suggests potential strategies for gene expression modulation to mitigate the effects of emotional eating. Adopting a 'One Health' approach by creating an evidence base derived from both human and animal studies is crucial for understanding how to control obesity.

Intuitive eating in the COVID-19 era: a study with university students in Brazil

BackgroundThe recurrence of weight gain is attributed to the homeostatic regulation of hunger and satiety signals, influenced by metabolic state, nutrient availability, and non-homeostatic mechanisms shaped by reinforced consequences from experiences. In response, Evelyn Tribole and Elyse Resch proposed Intuitive Eating (IE) in 1980, countering restrictive diets. IE, inversely correlated with Body Mass Index (BMI), binge eating, and anxiety/depression symptoms, fosters mind–body-food harmony by recognizing hunger and satiety cues. IE encourages meeting physiological, not emotional, needs, permitting unconditional eating, and relying on internal signals for food decisions. Amidst university students’ stress, exacerbated during the COVID-19 pandemic, understanding their eating behavior, particularly intuitive eating levels, becomes crucial.ObjectiveThis study aimed to assess the IE level of Brazilian students during the COVID-19 pandemic.MethodsThis cross-sectional study, the first to analyze the Intuitive Eating of students in Brazil during the pandemic, was conducted using an online questionnaire.ResultsThe sample comprised 1335 students, most of whom were women (82.17%), with a mean age of 26.12 ± 7.9 years, and a healthy nutritional status (57.58%). The mean IE score was 3.2 ± 0.6. A significant association was found between the confinement situation, the type of housing unit, and the IE subscale-Unconditional Permission to Eat (p = 0.043). However, there was no association between the other subscales and the total IE scale. Regarding self-reported mental and eating disorders, the most frequent were anxiety (21.2%), depression (6.5%), and binge eating disorder (BED) (4.7%). IE was negatively associated with BED (B = − 0.66; p < .001), bulimia nervosa (B = − 0.58; p < .001), body mass index (BMI) (p < .001) and self-reported anxiety (B = − .102; p = 0.16). The male sex showed a higher IE score compared with the female sex (p < .001).ConclusionWhile no significant association was found between IE and the confinement situation, a significant association was found between housing type and the Unconditional Permission to Eat subscale.

β-Glucan-based superabsorbent hydrogel acts as a gastrointestinal exoskeleton enhancing satiety and interfering fat hydrolysis

Fat and its hydrolysis products, fatty acids, are indispensable nutritional components; however, prolonged excessive fat consumption, particularly in western diets, contributes to the onset of obesity and multiple metabolic disorders. In this study, we propose a daily-ingestible hydrogel (denoted as βC-MA hydrogel) composed of natural β-glucan and sodium carboxymethylcellulose crosslinked by malic acid at 120 °C. This hydrogel exhibits rapid swelling performance, up to 24-fold within 1 min and 176-fold after 1 h in deionized water. It also lengthens gastric retention and increases endogenous satiety signal levels, potentially controlling appetite and reducing food intake. Furthermore, βC-MA hydrogels that enter the small intestine can effectively inhibit fat hydrolysis and decrease triglyceride synthesis and transport. Specifically, the hydrogels inhibit the release of free fatty acids (FFAs) by approximately 50 % during digestion, influence the translocation of triglycerides and FFAs across the intestinal epithelium, and reduce the serum triglyceride levels by 22.2 %. These findings suggest that βC-MA hydrogels could serve as a noninvasive gastrointestinal device for weight control, with the advantage of reducing food intake and restoring lipid metabolism homeostasis.

Circulating profile of the appetite-regulating hormone ghrelin during moult-fast and chick provisioning in southern rockhopper penguins (Eudyptes chrysocome chrysocome)

A multitude of animal species undergo prolonged fasting events at regularly occurring life history stages. During such periods of food deprivation, individuals need to suppress their appetite. The satiety signalling gut hormone ghrelin has received much attention in this context in studies looking at mammalian systems. In wild birds, however, knowledge on the ghrelin system and its role during extended fasts is still scarce. In this study, we collected plasma samples for measurements of circulating ghrelin concentrations from adult southern rockhopper penguins (Eudyptes chrysocome chrysocome) during the three to four week-long moult-fast that they repeat annually to replace their feathers. We further sampled chicks before and after feeding bouts and non-moulting adults. Circulating ghrelin levels did not differ significantly between fed and unfed chicks but chicks had significantly lower plasma ghrelin levels compared to adults. Furthermore, penguins in late moult (i.e. individuals at the end of the prolonged fasting bout) had higher ghrelin levels compared to non-moulting adults. Our results show elevated levels of circulating ghrelin during moult and generally lower levels of ghrelin in chicks than in adults regardless of feeding state. Given the scarcity or absence of knowledge on the function of ghrelin in seabirds and in fasting birds in general, our results add greatly to our understanding of the avian ghrelin system.

Hypothalamic AgRP neurons regulate the hyperphagia of lactation

ObjectiveThe lactational period is associated with profound hyperphagia to accommodate the energy demands of nursing. These changes are important for the long-term metabolic health of the mother and children as altered feeding during lactation increases the risk of mothers and offspring developing metabolic disorders later in life. However, the specific behavioral mechanisms and neural circuitry mediating the hyperphagia of lactation are incompletely understood. MethodsHere, we utilized home cage feeding devices to characterize the dynamics of feeding behavior in lactating mice. A combination of pharmacological and behavioral assays were utilized to determine how lactation alters meal structure, circadian aspects of feeding, hedonic feeding, and sensitivity to hunger and satiety signals in lactating mice. Finally, we utilized chemogenetic, immunohistochemical, and in vivo imaging approaches to characterize the role of hypothalamic agouti-related peptide (AgRP) neurons in lactational-hyperphagia. ResultsThe lactational period is associated with increased meal size, altered circadian patterns of feeding, reduced sensitivity to gut-brain satiety signals, and enhanced sensitivity to negative energy balance. Hypothalamic AgRP neurons display increased sensitivity to negative energy balance and altered in vivo activity during the lactational state. Further, using in vivo imaging approaches we demonstrate that AgRP neurons are directly activated by lactation. Chemogenetic inhibition of AgRP neurons acutely reduces feeding in lactating mice, demonstrating an important role for these neurons in lactational-hyperphagia. ConclusionsTogether, these results show that lactation collectively alters multiple components of feeding behavior and position AgRP neurons as an important cellular substrate mediating the hyperphagia of lactation.

Fatty Acid Desaturase Bmdesat5, Suppressed in the Salivary Glands by Domestication, is Involved in Regulation of Food Intake in Silkworms.

Understanding the evolutionary genetics of food intake regulation in domesticated animals has relevance to evolutionary biology, animal improvement, and obesity treatment. Here, we observed that the fatty acid desaturase gene (Bmdesat5), which regulates food intake, is suppressed in domesticated silkworms, but expressed in the salivary glands of the wild silkworm Bombyx mandarina. The content of its catalytic product, cis-vaccenic acid, was related to the expression levels of Bmdesat5 in the salivary glands of domesticated and wild silkworm strains. These two strains also showed significant differences in food intake. Using orally administering cis-vaccenic acid and transgenic-mediated overexpression, we verified that cis-vaccenic acid functions as a satiation signal, regulating food intake and growth in silkworms. Selection analysis showed that Bmdesat5 experienced selection, especially in the potential promoter, 5'-untranslated, and intron regions. This study highlights the importance of the decrement of satiety in silkworm domestication and provides new insights into the potential involvement of salivary glands in the regulation of satiety in animals, by acting as a supplement to gut-brain nutrient signaling.

Obesity-induced tissue alterations resist weight loss: A mechanistic review.

Interventions aimed at weight control often have limited effectiveness in combating obesity. This review explores how obesity-induced dysfunction in white (WAT) and brown adipose tissue (BAT), skeletal muscle, and the brain blunt weight loss, leading to retention of stored fat. In obesity, increased adrenergic stimulation and inflammation downregulate β-adrenoreceptors and impair catecholaminergic signalling in adipocytes. This disrupts adrenergic-mediated lipolysis, diminishing lipid oxidation in both white and brown adipocytes, lowering thermogenesis and blunting fat loss. Emerging evidence suggests that WAT fibrosis is associated with worse weight loss outcomes; indeed, limiting collagen and laminin-α4 deposition mitigates WAT accumulation, enhances browning, and protects against high-fat-diet-induced obesity. Obesity compromises mitochondrial oxidative capacity and lipid oxidation in skeletal muscle, impairing its ability to switch between glucose and lipid metabolism in response to varying nutrient levels and exercise. This dysfunctional phenotype in muscle is exacerbated in the presence of obesity-associated sarcopenia. Additionally, obesity suppresses sarcolipin-induced sarcoplasmic reticulum calcium ATPase (SERCA) activation, resulting in reduced oxidative capacity, diminished energy expenditure, and increased adiposity. In the hypothalamus, obesity and overnutrition impair insulin and leptin signalling. This blunts central satiety signals, favouring a shift in energy balance toward energy conservation and body fat retention. Moreover, both obese animals and humans demonstrate impaired dopaminergic signalling and diminished responses to nutrient intake in the striatum, which tend to persist after weight loss. This may result in enduring inclinations toward overeating and a sedentary lifestyle. Collectively, the tissue adaptations described pose significant challenges to effectively achieving and sustaining weight loss in obesity.

Orally Ingested Self-Powered Stimulators for Targeted Gut-Brain Axis Electrostimulation to Treat Obesity and Metabolic Disorders.

Obesity is a significant health concern that often leads to metabolic dysfunction and chronic diseases. This study introduces a novel approach to combat obesity using orally ingested self-powered electrostimulators. These electrostimulators consist of piezoelectric BaTiO3 (BTO) particles conjugated with capsaicin (Cap) and aim to activate the vagus nerve. Upon ingestion by diet-induced obese (DIO) mice, the BTO@Cap particles specifically target and bind to Cap-sensitive sensory nerve endings in the gastric mucosa. In response to stomach peristalsis, these particles generate electrical signals. The signals travel via the gut-brain axis, ultimately influencing the hypothalamus. By enhancing satiety signals in the brain, this neuromodulatory intervention reduces food intake, promotes energy metabolism, and demonstrates minimal toxicity. Over a 3-week period of daily treatments, DIO mice treated with BTO@Cap particles show a significant reduction in body weight compared to control mice, while maintaining their general locomotor activity. Furthermore, this BTO@Cap particle-based treatment mitigates various metabolic alterations associated with obesity. Importantly, this noninvasive and easy-to-administer intervention holds potential for addressing other intracerebral neurological diseases.

Cholinergic Neurotransmission Controls Orexigenic Endocannabinoid Signaling in the Gut in Diet-Induced Obesity.

The brain bidirectionally communicates with the gut to control food intake and energy balance, which becomes dysregulated in obesity. For example, endocannabinoid (eCB) signaling in the small-intestinal (SI) epithelium is upregulated in diet-induced obese (DIO) mice and promotes overeating by a mechanism that includes inhibiting gut-brain satiation signaling. Upstream neural and molecular mechanism(s) involved in overproduction of orexigenic gut eCBs in DIO, however, are unknown. We tested the hypothesis that overactive parasympathetic signaling at the muscarinic acetylcholine receptors (mAChRs) in the SI increases biosynthesis of the eCB, 2-arachidonoyl-sn-glycerol (2-AG), which drives hyperphagia via local CB1Rs in DIO. Male mice were maintained on a high-fat/high-sucrose Western-style diet for 60 d, then administered several mAChR antagonists 30 min prior to tissue harvest or a food intake test. Levels of 2-AG and the activity of its metabolic enzymes in the SI were quantitated. DIO mice, when compared to those fed a low-fat/no-sucrose diet, displayed increased expression of cFos protein in the dorsal motor nucleus of the vagus, which suggests an increased activity of efferent cholinergic neurotransmission. These mice exhibited elevated levels of 2-AG biosynthesis in the SI, that was reduced to control levels by mAChR antagonists. Moreover, the peripherally restricted mAChR antagonist, methylhomatropine bromide, and the peripherally restricted CB1R antagonist, AM6545, reduced food intake in DIO mice for up to 24 h but had no effect in mice conditionally deficient in SI CB1Rs. These results suggest that hyperactivity at mAChRs in the periphery increases formation of 2-AG in the SI and activates local CB1Rs, which drives hyperphagia in DIO.

Nausea-induced suppression of feeding is mediated by central amygdala Dlk1-expressing neurons

The motivation to eat is suppressed by satiety and aversive stimuli such as nausea. The neural circuit mechanisms of appetite suppression by nausea are not well understood. Pkcδ neurons in the lateral subdivision of the central amygdala (CeA) suppress feeding in response to satiety signals and nausea. Here, we characterized neurons enriched in the medial subdivision (CeM) of the CeA marked by expression of Dlk1. CeADlk1 neurons are activated by nausea, but not satiety, and specifically suppress feeding induced by nausea. Artificial activation of CeADlk1 neurons suppresses drinking and social interactions, suggesting a broader function in attenuating motivational behavior. CeADlk1 neurons form projections to many brain regions and exert their anorexigenic activity by inhibition of neurons of the parabrachial nucleus. CeADlk1 neurons are inhibited by appetitive CeA neurons, but also receive long-range monosynaptic inputs from multiple brain regions. Our results illustrate a CeA circuit that regulates nausea-induced feeding suppression.