Regulation Of Satiety Research Articles

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 gut-brain axis in appetite, satiety, food intake, and eating behavior: Insights from animal models and human studies.

The gut-brain axis plays a pivotal role in the finely tuned orchestration of food intake, where both homeostatic and hedonic processes collaboratively control our dietary decisions. This interplay involves the transmission of mechanical and chemical signals from the gastrointestinal tract to the appetite centers in the brain, conveying information on meal arrival, quantity, and chemical composition. These signals are processed in the brain eventually leading to the sensation of satiety and the termination of a meal. However, the regulation of food intake and appetite extends beyond the realms of pure physiological need. Hedonic mechanisms, including sensory perception (i.e., through sight, smell, and taste), habitual behaviors, and psychological factors, exert profound influences on food intake. Drawing from studies in animal models and human research, this comprehensive review summarizes the physiological mechanisms that underlie the gut-brain axis and its interplay with the reward network in the regulation of appetite and satiety. The recent advancements in neuroimaging techniques, with a focus on human studies that enable investigation of the neural mechanisms underpinning appetite regulation are discussed. Furthermore, this review explores therapeutic/pharmacological strategies that hold the potential for controlling food intake.

The modulatory effect of oat on brain-derived neurotrophic factor, orexigenic neuropeptides, and dopaminergic signaling in obesity-induced rat model: a comparative study to orlistat.

Obesity is a non-communicable complex disease that is the fifth leading cause of death worldwide. According to a novel viewpoint, the brain plays a significant role in the central regulation of satiety and energy homeostasis. Because of its rich nutritional profile and versatile uses, oat (Avena sativa) is one of the most popular functional foods recommended by many nutritionists. The anti-obesity effect of oat was hypothesized, focusing on the brain as the target organ. In the current study, the interplay between brain biomarkers, obesity, and its related complications was evaluated in diet-induced obese rats for 25 weeks, in which 60 adult male white albino Wistar rats were divided into three control and seven treatment groups given oat extracts in a dose-dependent manner. Oat significantly improved obesity-related metabolic complications. In terms of brain function, oat significantly increased dopaminergic signaling, brain-derived neurotrophic factor levels, vaspin, irisin, and uncoupling protein-1 brain levels, while decreasing the expression of agouti-related peptide and neuropeptide Y (P-value < 0.05). The current study proposes oat supplementation as a new conceptual framework with numerous implications for hedonic and homeostatic mechanisms that control satiety. © 2024 Society of Chemical Industry.

The Contribution of the Brain-Gut Axis to the Human Reward System.

The human reward network consists of interconnected brain regions that process stimuli associated with satisfaction and modulate pleasure-seeking behaviors. Impairments in reward processing have been implicated in several medical and psychiatric conditions, and there is a growing interest in disentangling the underlying pathophysiological mechanisms. The brain-gut axis plays a regulatory role in several higher-order neurophysiological pathways, including reward processing. In this context, the aim of the current review was to critically appraise research findings on the contribution of the brain-gut axis to the human reward system. Enteric neuropeptides, which are implicated in the regulation of hunger and satiety, such as ghrelin, PYY3-36, and glucagon-like peptide 1 (GLP-1), have been associated with the processing of food-related, alcohol-related, and other non-food-related rewards, maintaining a delicate balance between the body's homeostatic and hedonic needs. Furthermore, intestinal microbiota and their metabolites have been linked to differences in the architecture and activation of brain reward areas in obese patients and patients with attention deficit and hyperactivity disorder. Likewise, bariatric surgery reduces hedonic eating by altering the composition of gut microbiota. Although existing findings need further corroboration, they provide valuable information on the pathophysiology of reward-processing impairments and delineate a novel framework for potential therapeutic interventions.

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.

Ketogenic Keys to Body Composition: Nutritional Insights and Comparative Dietary Effects

Background: The ketogenic diet, characterized by high fat, low carbohydrate intake, has garnered significant interest for its impact on body composition. Despite its popularity, the mechanisms and long-term effects of the diet remain subjects of ongoing research and debate within the medical and nutritional science communities.&#x0D; Methods: This review systematically examines peer-reviewed clinical trials, observational studies, and comparative analyses conducted from 2004 to 2024. Studies were selected based on their relevance to the ketogenic diet's effects on body composition, adherence to rigorous methodological standards, and the provision of clear outcome measures related to fat mass, lean muscle mass, and overall weight changes.&#x0D; Results: The review synthesizes findings to elucidate the diet's mechanisms, effects, and comparative performance against other dietary interventions. The ketogenic diet induces metabolic adaptations conducive to fat loss while potentially preserving lean muscle mass, mediated through ketosis and associated hormonal shifts. Comparative analyses suggest that the ketogenic diet may offer distinct advantages in fat reduction compared to low-fat and Mediterranean diets, attributed to its profound effects on metabolic pathways and satiety regulation. However, individual responses vary significantly, influenced by factors such as exercise, diet duration, macronutrient composition, and genetic predispositions.&#x0D; Conclusion: The ketogenic diet emerges as a potent intervention for altering body composition, particularly effective in reducing fat mass. Its unique metabolic and hormonal effects distinguish it from other dietary approaches. Nevertheless, considerations regarding the diet's long-term sustainability, potential risks, and individual variability underscore the need for personalized dietary planning and further research.

Neutrophil Gelatinase-Associated Lipocalin as a Biomarker in Post-Acute COVID-19 Syndrome.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) is part of the innate immune system and acute-phase protein. Current data state that acute COVID-19 patients have higher levels of serum NGAL (sNGAL), but it is not known if higher protein levels are maintained in the convalescents. As post-COVID complications are currently the most important aspect of the disease, further research into metabolic and immunological consequences of the disease is needed. Methods: We aimed to determine the levels of sNGAL in a patient population 3 months after the acute phase of the disease and to identify the factors that may be related to the elevation of sNGAL levels in the mentioned cohort. The study included 146 patients diagnosed with COVID-19 in different stages of the disease. Three months after COVID-19 diagnosis, patients' sera were sampled and tested. Results: We demonstrate an association between the severity of the disease in the acute phase and elevated sNGAL levels three months after recovery, with the exception of the most severe hospitalized patients, who received early treatment. Moreover, we establish that sNGAL levels could be associated with prolonged dyspnea and the regulation of hunger and satiety in COVID-19 convalescents. Conclusions: These observations support the view that the introduction of antiviral treatment, steroids, and intense oxygen therapy reduces post-COVID immune-associated complications.

Exercise-induced effects on asprosin and indices of atherogenicity and insulin resistance in males with metabolic syndrome: a randomized controlled trial

Metabolic syndrome (MetS) development is associated with insulin resistance and obesity, with the progression of visceral adipose tissue playing a crucial role. Excessive adipose tissue is accompanied by an increase in the asprosin (ASP), which is responsible for carbohydrate metabolism and the regulation of hunger and satiety. Exercise affects the release of ASP, which may regulate metabolism accordingly. Due to the inconclusive results of the effect of exercise on ASP concentration in men with MetS, 12-week interventions were carried out in the following groups: EG1—aerobic training (n = 21, age: 34.21 ± 6.06, WC; waist circumference: 114.7 ± 10.93) and EG2—a combination of aerobic and resistance training (n = 21, age: 37.37 ± 7.08, WC: 114.8 ± 11.64) and compared with a control group (CG) of men with MetS without any intervention (n = 20, age: 38.26 ± 7.43, WC: 115.3 ± 10.54). Body composition, indicators of carbohydrate-lipid metabolism, and ASP were assessed four times: before the intervention, at 6 and 12 weeks of training, and 4 weeks after the training sessions. A comparison of the intervention influence on changes in the analyzed variables between the groups was performed using ANOVA test for dependent groups with post-hoc comparison. The effect size (ES) was also assessed using squared eta (η2). The implementation of aerobic training resulted in a decrease in ASP concentration (p = 0.03) within 6 weeks of the intervention, while in the CG a gradual increase in ASP was confirmed (p < 0.001). Aerobic-resistance training did not induce significant changes in ASP concentration but resulted in an increase in fat-free mass/fat mass (FFM/FM) ratio (p < 0.001), and a decrease (p = 0.04) in Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). Changes in the visceral adipose tissue level indicate a gradual decrease in both the EG1 (p = 0.01) and EG2 (p = 0.04) groups. Both aerobic and aerobic-resistance exercises may have a regulatory effect, mainly by reducing visceral adipose tissue, on the improvement of metabolic disorders.

Endogenous Opioids in the Homeostatic Regulation of Hunger, Satiety, and Hedonic Eating: Neurobiological Foundations.

This chapter (part one of a trilogy) summarizes the neurobiological foundations of endogenous opioids in the regulation of energy balance and eating behavior, dysregulation of which translates to maladaptive dietary responses in individuals with obesity and eating disorders, including anorexia, bulimia, and binge eating disorder. Knowledge of these neurobiological foundations is vital to researchers' and clinicians' understanding of pathophysiology as well as the science-based development of multidisciplinary diagnoses and treatments for obesity and eating disorders. We highlight mechanisms of endogenous opioids in both homeostatic and hedonic feeding behavior, review research on the dysregulation of food reward that plays a role in a wide array of obesity and disordered eating, and the clinical implications of neurobiological responses to food for current science-based treatments for obesity and eating disorders.

Food cue reward salience does not explain Hyperphagia in adolescents with Prader-Willi syndrome

ABSTRACT Prader-Willi Syndrome (PWS) is characterized by hyperphagia, an extreme and persistent hunger that emerges in early childhood. We used event-related potentials (ERPs) to objectively investigate brain responses to low- and high-calorie foods, animals, and household objects in 20 satiated adolescents with PWS. Late Positive Potential (LPP) responses to food images did not differ from non-food images. Rather, we observed larger ERPs to high-calorie foods relative to animal images (p=.001) in an earlier time window. These responses correlated with greater severity of hyperphagia (p = .01). Thus, hyperphagia associated with PWS may be due to altered satiety regulation rather than increased motivational salience.

Uroguanylin prevents hepatic steatosis, mitochondrial dysfunction and fibrosis in obesity-associated NAFLD.

The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguanylin and guanylin, two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of obesity-associated NAFLD after bariatric surgery. Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 214 participants undergoing bariatric surgery with biopsy-proven NAFLD diagnosis. Pathways involved in lipid metabolism, mitochondrial network and fibrogenesis were evaluated in liver biopsies (n=137). The effect of guanylin and uroguanylin on these metabolic functions was assessed in HepG2 hepatocytes and LX-2 hepatic stellate cells (HSC) under lipotoxic and profibrogenic conditions. Plasma and hepatic expression of GUCA2B were decreased in obesity-associated NAFLD. Both GUCA2A and GUCA2B levels were increased after sleeve gastrectomy and Roux-en-Y gastric bypass in parallel to the improved liver function. The liver of patients with type 2 diabetes showed impaired mitochondrial β-oxidation, biogenesis, dynamics as well as increased fibrosis. Uroguanylin diminished the lipotoxicity in palmitate-treated HepG2 hepatocytes, evidenced by decresased steatosis and lipogenic factors, as well as increased mitochondrial network expression, AMPK-induced β-oxidation and oxygen consumption rate. Additionally, uroguanylin, but not guanylin, reversed HSC myofibroblast transdifferentiation as well as fibrogenesis after TGF-β1 stimulation. Uroguanylin constitutes a protective factor against lipotoxicity, mitochondrial dysfunction and fibrosis. Increased GUCA2B levels might contribute to improve liver injury in patients with obesity-associated NAFLD after bariatric surgery.

Adequate fruit and vegetable consumption and its association with overnutrition among primary school-aged children

Overnutrition among school-aged children increases substantially over the last decade. Among the direct causes of overweight/obesity is inadequate intake of fruit and vegetable. Prior studies have shown that fruit and vegetable (FV) is not merely the main source of vitamins andminerals, but also playing role on preventing weight gain through satiety regulation. This study aims to determine the association of FV consumption adequacy among 5-12 years schoolers and their overnutrition status. This cross-sectional study was conducted in Jakarta and Depok, carried out on 57 children who filled out an online questionnaire survey. Respondents’ characteristics were obtained through the self-administered online questionnaire. BMI for age z-score (BAZ) was calculated from the self-reported recall of body weight and height. The FV consumption was evaluated using the WHO STEP-wise questionnaire. Respondent’s characteristics were presented in frequency and percentage, while association test was done using Fisher Exact test (CI 95%). In this study, 40,4% of children were overweight and most children did not consume adequate portions of fruit and vegetable (73,7% and 57,9%, respectively). There are no significant association between FV consumption and children’s overnutrition (p= 0,171 and p= 0,788, respectively; CI 95%). Overall, a high proportion of children overnutrition was observed. However, there is no significant association was found between fruit and vegetable consumption and children’s overnutrition. There is a need for specific regulations and practices that may engage children in consuming fruit and vegetable on the daily basis.

Rare genetic forms of obesity in childhood and adolescence, a comprehensive review of their molecular mechanisms and diagnostic approach.

Obesity represents a major health problem in the pediatric population with an increasing prevalence worldwide, associated with cardiovascular and metabolic disorders, and due to both genetic and environmental factors. Rare forms of obesity are mostly monogenic, and less frequently due to polygenic influence. Polygenic form of obesity is usually the common obesity with single gene variations exerting smaller impact on weight and is commonly non-syndromic.Non-syndromic monogenic obesity is associated with variants in single genes typically related to the hypothalamic leptin-melanocortin signalling pathway, which plays a key role in hunger and satiety regulation, thus body weight control. Patients with these genetic defects usually present with hyperphagia and early-onset severe obesity. Significant progress in genetic diagnostic testing has recently made for early identification of patients with genetic obesity, which guarantees prompt intervention in terms of therapeutic management of the disease. What is Known: • Obesity represents a major health problem among children and adolescents, with an increasing prevalence worldwide, associated with cardiovascular disease and metabolic abnormalities, and it can be due to both genetic and environmental factors. • Non-syndromic monogenic obesity is linked to modifications in single genes usually involved in the hypothalamic leptin-melanocortin signalling pathway, which plays a key role in hunger and satiety regulation. What is New: • The increasing understanding of rare forms of monogenic obesity has provided significant insights into the genetic causes of pediatric obesity, and our current knowledge of the various genes associated with childhood obesity is rapidly expanding. • A useful diagnostic algorithm for early identification of genetic obesity has been proposed, which can ensure a prompt intervention in terms of therapeutic management of the disease and an early prevention of the development of associated metabolic conditions.

Endocrinology of Underweight and Anorexia Nervosa.

More than any other mental illness, the course, prognosis, and therapy of anorexia nervosa are shaped by the physical changes associated with being underweight. This article provides an overview of the endocrine changes associated with malnutrition and underweight. This overview serves as a basis for understanding the other articles in this special issue, which deal with the health risks associated with being underweight. In this context, the differences between underweight in anorexia nervosa and in constitutional thinness are of particular importance in assessing the impact of intentional weight loss. In this context, the regulation of hunger and satiety deserves special interest, as this is the area in which the intentional influence on body weight comes into play. Clinical consequences on, for example, fertility, bone metabolism, the homeostasis of, for example, serum glucose levels, or body temperature have been observed for a long time; nonetheless, the medical responses, apart from vitamin supplementations and advice to gain weight, are still limited. Therefore, emphasis was placed on the potential improvement of outcomes through the administration of central or peripheral hormones. Studies were identified on PubMed via a selection of relevant keywords; original texts that were cited in reviews were studied where it was advantageous. This review found some promising data on bone health and the administration of transdermal oestrogen, which is not yet widely used, as well as distinct hormonal markers to differentiate between CT and AN. We concluded that the continuous efforts to investigate the role of endocrinology in underweight and/or anorexia nervosa lead to outcome benefits and that more and higher-powered studies are needed.

Independent effects of posttraumatic stress disorder diagnosis and metabolic syndrome status on prefrontal cortical thickness and subcortical gray matter volumes.

Posttraumatic stress disorder (PTSD) and metabolic syndrome (MetS) are associated with overlapping brain structural differences. These often involve brain structures involved in the regulation of appetite, food intake, satiety, and reward processing. We examined the individual and interactive effects of PTSD diagnosis and MetS on cortical thickness and subcortical gray matter volumes in patients with PTSD (n = 104) compared to trauma-exposed controls (n = 97). Multivariate models were constructed for FreeSurfer-generated prefrontal cortical thickness and subcortical gray matter regions-of-interest (ROIs) to explore the effects of PTSD diagnosis and MetS as predictors, adjusting for relevant socio-demographic and clinical covariates. Individual prefrontal cortical and subcortical limbic ROIs were also selected based on apriori evidence of their involvement in both PTSD and MetS. The mean age of the sample (n = 201; 78% female) was 41.6 (SD, 13.1) years. PTSD and MetS status showed independent associations with prefrontal cortical thickness and subcortical gray matter volumes across multiple ROIs, adjusting for age, sex, scanner sequence, alcohol, and tobacco use. PTSD and MetS are independently associated with brain structural differences, including thinner prefrontal cortical thickness and smaller subcortical gray matter volumes, across multipleROIs implicated in the hedonic and homeostatic regulation of food intake.

Leptin, but not ghrelin, is associated with food addiction scores in a population-based subject sample.

Ghrelin and leptin are both peptide hormones and act as opposing players in the regulation of hunger, satiety and energy expenditure. Leptin reduces appetite and feelings of hunger and is secreted mainly by adipocytes, while ghrelin increases appetite and food intake and reduces metabolic rate. Both hormones have been implicated in addictive disorders. Ghrelin was shown to have pro-addictive effects while leptin's role in addiction yields more conflicting results. Their involvement in the regulation of both food intake and addictive behaviors make them interesting candidates when investigating the regulation of food addiction. However, only few human studies have been performed and large-scale studies are lacking to date. We aimed to investigate the association between total ghrelin and leptin serum levels with scores in the Yale Food Addiction Scale (YFAS). Subjects were recruited in the LIFE Adult cohort. 909 subjects were included in the analysis and we performed univariate multiple linear regression models, adjusted for age, sex (in total group analyses only), alcohol consumption, smoking status, BMI scores, cortisol concentrations, Center for Epidemiological Studies Depression Scale (CES-D) and the 7-item Generalized Anxiety Disorder Scale (GAD-7) sum scores. The dependent variable was the YFAS score. In men, leptin serum levels showed a significant positive association (standardized β = 0.146; p = 0.012) with the YFAS score. This finding was confirmed in an extreme-group comparison: men in the highest quartile of leptin levels had significantly higher YFAS sum scores than men in the lowest quartile (1.55 vs. 1.18; p = 0.00014). There was no association with YFAS sum score in the total group (standardized β = -0.002; p = 0.974) or in women (standardized β = -0.034; p = 0.674). Total serum ghrelin showed no association with YFAS sum score neither in the total group (standardized β = -0.043; p = 0.196) nor in men (n = 530; standardized β = -0.063; p = 0.135) or women (n = 379; standardized β = -0.035; p = 0.494). Our findings are in line with previous literature and suggest that total ghrelin serum levels are not associated with food addiction scores. Leptin had been previously shown to be associated with food addiction and we confirmed this finding for men in a large, population-based approach.

Early-set POMC methylation variability is accompanied by increased risk for obesity and is addressable by MC4R agonist treatment.

Increasing evidence points toward epigenetic variants as a risk factor for developing obesity. We analyzed DNA methylation of the POMC (pro-opiomelanocortin) gene, which is pivotal for satiety regulation. We identified sex-specific and nongenetically determined POMC hypermethylation associated with a 1.4-fold (confidence interval, 1.03 to 2.04) increased individual risk of developing obesity. To investigate the early embryonic establishment of POMC methylation states, we established a human embryonic stem cell (hESC) model. Here, hESCs (WA01) were transferred into a naïve state, which was associated with a reduction of DNA methylation. Naïve hESCs were differentiated via a formative state into POMC-expressing hypothalamic neurons, which was accompanied by re-establishment of DNA methylation patterning. We observed that reduced POMC gene expression was associated with increased POMC methylation in POMC-expressing neurons. On the basis of these findings, we treated POMC-hypermethylated obese individuals (n = 5) with an MC4R agonist and observed a body weight reduction of 4.66 ± 2.16% (means ± SD) over a mean treatment duration of 38.4 ± 26.0 weeks. In summary, we identified an epigenetic obesity risk variant at the POMC gene fulfilling the criteria for a metastable epiallele established in early embryonic development that may be addressable by MC4R agonist treatment to reduce body weight.

The impact of olfactory and gustatory perception on metabolic homeostasis in obese patients

Obesity is currently a major global public health problem. As a result, in recent decades there has been a growing interest in studying the impact of this disease on the functioning of the central nervous system. One of the least understood aspects is the impact that obesity has on sensory systems.The olfactory and gustatory systems are closely related to various vital functions, such as the nocifensors activation, the stimulation of digestive reflexes. In addition, these sensory systems are known to play an important role in the mechanisms of food consumption through the regulation of appetite and satiety, influencing food choice and, therefore, they are involved in the development of obesity. A number of clinical studies have shown that obese patients are more likely to suffer from hyposmia compared to lean people of the same age.The reasons why this relationship exists remain largely unclear. The aim of this review is to assess the available data on this topic and to identify new promising areas for further research. The review was conducted in the PubMed databases for 2017–2023.

Structure-Activity Relationship Study of the High-Affinity Neuropeptide Y4 Receptor Positive Allosteric Modulator VU0506013.

Positive allosteric modulators targeting the Y4 receptor (Y4R), a G protein-coupled receptor (GPCR) involved in the regulation of satiety, offer great potential in anti-obesity research. In this study, we selected 603 compounds by using quantitative structure-activity relationship (QSAR) models and tested them in high-throughput screening (HTS). Here, the novel positive allosteric modulator (PAM) VU0506013 was identified, which exhibits nanomolar affinity and pronounced selectivity toward the Y4R in engineered cell lines and mouse descending colon mucosa natively expressing the Y4R. Based on this lead structure, we conducted a systematic SAR study in two regions of the scaffold and presented a series of 27 analogues with modifications in the N- and C-terminal heterocycles of the molecule to obtain insight into functionally relevant positions. By mutagenesis and computational docking, we present a potential binding mode of VU0506013 in the transmembrane core of the Y4R. VU0506013 presents a promising scaffold for developing in vivo tools to move toward anti-obesity drug research focused on the Y4R.

Genetics: A Starting Point for the Prevention and the Treatment of Obesity.

Obesity is a common, serious, and costly disease. More than 1 billion people worldwide are obese-650 million adults, 340 million adolescents, and 39 million children. The WHO estimates that, by 2025, approximately 167 million people-adults and children-will become less healthy because they are overweight or obese. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer. These are among the leading causes of preventable, premature death. The estimated annual medical cost of obesity in the United States was nearly $173 billion in 2019 dollars. Obesity is considered the result of a complex interaction between genes and the environment. Both genes and the environment change in different populations. In fact, the prevalence changes as the result of eating habits, lifestyle, and expression of genes coding for factors involved in the regulation of body weight, food intake, and satiety. Expression of these genes involves different epigenetic processes, such as DNA methylation, histone modification, or non-coding micro-RNA synthesis, as well as variations in the gene sequence, which results in functional alterations. Evolutionary and non-evolutionary (i.e., genetic drift, migration, and founder's effect) factors have shaped the genetic predisposition or protection from obesity in modern human populations. Understanding and knowing the pathogenesis of obesity will lead to prevention and treatment strategies not only for obesity, but also for other related diseases.