Precision nutrition is a vibrant and rapidly evolving field of scientific research and innovation with the potential to deliver health, societal and economic benefits by improving healthcare delivery and policies. Advances in deep phenotyping technologies, digital tools and artificial intelligence have made possible early proof-of-concept research that expands the understanding of within- and between-person variability in responses to diet. These studies illustrate the promise of precision nutrition to complement the traditional 'one size fits all' dietary guidelines, which, while considering broad life-stage and disease-specific nutritional requirements, often lack the granularity to account fully for individual variations in nutritional needs and dietary responses. Despite these developments, however, considerable challenges remain before precision nutrition can be implemented on a broader scale. This Review examines the current state of precision nutrition research, with a focus on its application to reducing the incidence and burden of cardiometabolic diseases. We critically examine the evidence base, explore the potential benefits and discuss the challenges and opportunities ahead.

Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score-a measure of obesity-in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B (DENND1B). Each copy of the alternate allele was associated with ~7.5% greater body fat. We demonstrate a role for this gene in regulating signaling and trafficking of melanocortin 4 receptor, a critical controller of energy homeostasis. Thus, canine genetics identified obesity genes and mechanisms relevant to both dogs and humans.

Obesity-related genetic disorders are marked by severe, early-onset obesity caused by mutations that disrupt key biological mechanisms regulating hunger, energy balance, and fat storage. These disorders commonly impact systems such as the hypothalamic leptin-melanocortin signaling network, which plays a crucial role in controlling appetite and body weight, mainly through the melanocortin-4 receptor (MC4R) pathway. This review explores current management strategies and emerging therapies for genetic obesity disorders, highlighting the importance of treatment approaches and expanded genetic diagnostics to improve outcomes for affected individuals.

In modern society, excessive nutrient intake from food is a major factor contributing to the development of a series of metabolic disorders and cardiovascular diseases. Further investigation of the mechanisms underlying nutrient absorption in the intestine will help to better understand and develop preventive or therapeutic strategies. In this study, using receptor-interacting protein kinase 1 (Ripk1) intestine-specific heterozygous knockout mice (Ripk1 IEC+/-) and high-fat diet (HFD)-feeding mouse model, we report that HFD-induced shift in the transcriptional profile of the ileum toward that of the jejunum, characterized by increased expression of jejunal feature genes in the ileum, are attenuated in Ripk1 IEC+/- female mice, but not in males. Accordingly, HFD-induced metabolic disorders, including obesity, impaired glucose tolerance, insulin resistance, and dyslipidemia, are significantly ameliorated in the Ripk1 IEC+/- female mice. These findings demonstrate a new, sex-specific intestinal regulatory mechanism and highlight the critical role of intestinal RIPK1 in regulating HFD-induced metabolic disorders in females.

The global prevalence of obesity has more than doubled over the past four decades, currently affecting more than a billion individuals. Beyond its recognition as a high-risk condition that is causally linked to many chronic illnesses, obesity has been declared a disease per se that results in impaired quality of life and reduced life expectancy. Notably, two-thirds of obesity-related excess mortality is attributable to cardiovascular disease. Despite the increasingly appreciated link between obesity and a broad range of cardiovascular disease manifestations including atherosclerotic disease, heart failure, thromboembolic disease, arrhythmias, and sudden cardiac death, obesity has been underrecognized and sub-optimally addressed compared with other modifiable cardiovascular risk factors. In the view of major repercussions of the obesity epidemic on public health, attention has focused on population-based and personalized approaches to prevent excess weight gain and maintain a healthy body weight from early childhood and throughout adult life, as well as on comprehensive weight loss interventions for persons with established obesity. This clinical consensus statement by the European Society of Cardiology discusses current evidence on the epidemiology and aetiology of obesity; the interplay between obesity, cardiovascular risk factors and cardiac conditions; the clinical management of patients with cardiac disease and obesity; and weight loss strategies including lifestyle changes, interventional procedures, and anti-obesity medications with particular focus on their impact on cardiometabolic risk and cardiac outcomes. The document aims to raise awareness on obesity as a major risk factor and provide guidance for implementing evidence-based practices for its prevention and optimal management within the context of primary and secondary cardiovascular disease prevention.

Obesity is a highly prevalent chronic disease and major driver of both atherosclerotic heart disease and heart failure. Obesity is also a heritable neuronal disease with heritability estimates of up to 70%. In this work I review how common genetic variants, usually with small effect sizes, contribute to the risk for developing obesity and cardiometabolic disease in the majority of people and how this can be further modulated by environmental factors. In some individuals, rare genetic variants with large effect sizes can influence the risk of developing obesity, in some cases in a Mendelian manner. I also address how identification of these rare variants has led to fundamental biologic insights into how satiety and reward are biologic processes, has led to more personalized treatments, and has identified potential novel drug treatments. Biologic insights derived from genetic studies of obesity have also improved our understanding of the causal mediators between obesity and cardiovascular disease. A major limitation of studies to date is that they involved mostly people of European ancestry. Studying more diverse populations will improve our understanding of obesity and cardiometabolic disease. Lessons derived from genetic studies make a compelling case for increasing accessibility to therapies that have sustained efficacy in managing obesity and improving health. This increased knowledge must also inform public health initiatives that will reduce the prevalence of obesity in the coming decades.

A neural circuit in mice mediates the preference for high-sugar food after a meal.

Major depressive disorder is a common, disabling mental disorder characterized by extensive etiological and phenotypic heterogeneity. This heterogeneity makes treatment approaches imprecise and often ineffective. Insight into the underlying biological mechanisms underpinning depression and its subtypes may enable more personalized treatments. In this review, we provide an overview of immuno-metabolic depression and illustrate that significant immuno-metabolic dysregulations are present in about 20-30% of people with depression. Such immuno-metabolic depression is characterized by the clustering of 1) atypical, energy-related depressive symptoms such as hypersomnia, fatigue, hyperphagia, and possibly anhedonia, 2) systemic low-grade inflammation with elevated levels of e.g., C-reactive protein, cytokines and glycoprotein acetyls, and 3) metabolic abnormalities involving e.g., obesity, dyslipidaemia, insulin and leptin resistance. Persons with immuno-metabolic depression are at a higher risk for cardiometabolic diseases and seem to respond less well to standard antidepressant treatment. Interventions targeting inflammation, metabolism or lifestyle may be more effective treatment options for individuals with immuno-metabolic depression, in line with principles of precision psychiatry.

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has been shown to reduce hunger and weight in patients aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1 [PCSK1]), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS). No approved therapies for patients younger than 6 years old currently exist. The phase 3, open-label VENTURE trial aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2-5 years with POMC or LEPR deficiency or BBS.

This phase 3, open-label, multicentre trial, conducted across six sites in the USA, the UK, Spain, and Australia, enrolled eligible patients aged 2-5 years who had hyperphagia and obesity due to biallelic POMC (including PCSK1) or LEPR variants or genetically confirmed BBS. Open-label subcutaneous setmelanotide was administered once daily for 52 weeks, starting at 0·5 mg with doses increasing every 2 weeks in 0·5 mg increments until reaching the maximum dose based on weight. The co-primary endpoints at week 52 were the percentage of patients reaching a 0·2-point decrease or greater in BMI Z score (a statistical measure used to assess BMI in paediatric patients considering a patient's BMI and comparing it to reference values for the same age and sex) and mean percent change in BMI. Additional endpoints measured safety, hunger, weight-related outcomes, and caregiver burden. The study is registered at ClinicalTrials.gov (NCT04966741) and is complete.

Between March 8, 2022, and Sept 18, 2023, 13 patients were screened at the six sites, and 12 patients were enrolled in the study (seven with POMC or LEPR and five with BBS); one patient with BBS was excluded as their BMI was not at the 97th percentile or above. Of the 12 patients enrolled, most were male (seven [58%] vs five [42%] for female) and the mean age was 3·6 years (SD 0·9). 11 patients completed the trial. Ten (83%) of the 12 overall participants reached a 0·2-point reduction or more in BMI Z score per WHO methodology at week 52 (95% CI 58·7-99·8). The mean percent change in BMI from baseline at week 52 was -18% (SD 13) in the overall safety population. Mean percent change in BMI at week 52 was -26% (SD 11) in patients with POMC or LEPR deficiency and -10% (9) in patients with BBS. Mean reductions in secondary endpoints of BMI Z score (3·4 [2·5]) and percent of the BMI 95th percentile (32·5 [22·9]) were seen at Week 52. 91% of caregivers reported that patients were less hungry than at baseline. All adverse events were mild or moderate; skin hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infection, and injection site reactions were most common. No serious adverse events or adverse events leading to study discontinuation or death were reported.

To our knowledge this is the first trial of setmelanotide in patients younger than 6 years old. These results support the benefit of the drug as an early intervention to manage obesity in this population.

Rhythm Pharmaceuticals.

Menopausal syndrome profoundly affects the physical and mental health of many women, drawing increasing attention from the medical community. However, its pathogenesis remains unclear. These symptoms are primarily driven by hormonal fluctuation. The hypothalamus, a key regulator of hormonal balance, potentially playing a critical role in the manifestation of menopausal syndrome.

We simulated the low-estrogen menopausal state using ovariectomized rats, confirmed the success of ovariectomy via histological analysis of the uterus and vagina, followed by estrogen treatment. TMT-labeled quantitative proteomics, RTqPCR, targeted proteomics and Western blotting were used to identify differentially expressed proteins and their functions in the hypothalamus under low-estrogen conditions.

One-way ANOVA (p < 0.05) identified 295 differentially expressed proteins across the sham, ovariectomized and estrogen-treated groups. Post-ovariectomy, 103 differentially expressed proteins were upregulated and 93 were downregulated. Among these, 50 proteins were involved in hormones and neurotransmitters, immunity, metabolism and cardiovascular function. Notably, four proteins-Prkcg, Hsp90ab1, Ywhae, and Gad2-were identified as crucial regulators.

This study elucidates the central molecular mechanism of menopausal syndrome through bioinformatics analysis of differentially expressed proteins in the hypothalamus under low-estrogen conditions, providing novel targets for the treatment of related symptoms.

Obesity is associated with the gut microbiome. Here, we report that gut commensal Clostridia bacteria regulate host energy balance through the tryptophan-derived metabolite indole-3-propionic acid (IPA). IPA acts as an endogenous leptin sensitiser to counteract obesity. Mechanistically, IPA is secreted from the gut into the circulation, and then targets to the STAT3 in the hypothalamic appetite regulation centre, promoting its phosphorylation and nuclear translocation, which enhances the body's response to leptin, and regulates the balance between appetite and energy metabolism. The in vitro pull-down assays involving site-directed mutagenesis demonstrate that Trp623 in the SH2 domain is the key binding site for STAT3-IPA interaction. High-fat diet (HFD), rather than genetic factors, induces excessive secretion of antimicrobial peptides by Paneth cells, inhibiting the growth of Clostridia in the gut and resulting in decreased production of the beneficial metabolite IPA. IPA or Clostridium sporogenes supplement effectively controls weight gain, improves glucose metabolism, and reduces inflammation in DIO mice. IPA fails to achieve such effects in ob/ob mice, while exogenous leptin administration restores the therapeutic effect of IPA. Our study suggests that the IPA-based gut-brain axis regulates host metabolism, and supplementation with microbiome-derived IPA could be a promising intervention strategy for treating obesity.

The prevalence of obesity continues to rise, and public health dietary recommendations are not being adhered to. The transition to higher education is a period of risk for weight gain in young adults and has been demonstrated as a good time to initiate behaviour change. A genotype-based personalised approach to dietary recommendations may motivate young adults to maintain or adopt positive dietary behaviours. The aim of the present study was to determine the efficacy of genotype-based personalised dietary and physical activity advice on healthy eating motivation in young adults. Participants were young adults (n = 153), aged 18-25 years. Baseline measures (participant characteristics, height, weight, body mass index [BMI], body fat percentage [BF%], healthy eating motivation and physical activity) were collected. Participants were genotyped for a SNP in the FTO gene (rs99396090) and randomly allocated (stratified for genotype) to three different groups (1. Genotype-based personalised advice: dietary and physical activity advice based on genotype, BMI and reported physical activity; 2. Non-genotype-based personalised advice: dietary and physical activity advice based on BMI and reported physical activity; 3. Control: no advice). A week after receipt of advice delivered via email, participants completed the healthy eating motivation questionnaire for a second time. Genotype-based personalised dietary advice did not affect healthy eating motivation: when participants were analysed across the whole group (p = 0.417), when analysed according to those informed of a risk or non-risk-associated genotype (p = 0.287), or when analysed according to those with a BMI (>25 kg/m2; p = 0.336) or BF% (male >18%, female >31%; p = 0.387) outside the healthy range. There was also no significant difference in healthy eating motivation at 1-week in the control or non-genotype-based advice groups. Genotype-based personalised advice for the prevention of obesity did not affect healthy eating motivation in this group of healthy, young adults.

Genome-wide association studies (GWAS) have identified thousands of loci for disease-related human traits in cross-sectional data. However, the impact of age on genetic effects is underacknowledged. Also, identifying genetic effects on longitudinal trait change has been hampered by small sample sizes for longitudinal data. Such effects on deteriorating trait levels over time or disease progression can be clinically relevant.

Under certain assumptions, we demonstrate analytically that genetic-by-age interaction observed in cross-sectional data can be indicative of genetic association on longitudinal trait change. We propose a 2-stage approach with genome-wide pre-screening for genetic-by-age interaction in cross-sectional data and testing identified variants for longitudinal change in independent longitudinal data. Within UK Biobank cross-sectional data, we analyze 8 complex traits (up to 370,000 individuals). We identify 44 genetic-by-age interactions (7 loci for obesity traits, 26 for pulse pressure, few to none for lipids). Our cross-trait view reveals trait-specificity regarding the proportion of loci with age-modulated effects, which is particularly high for pulse pressure. Testing the 44 variants in longitudinal data (up to 50,000 individuals), we observe significant effects on change for obesity traits (near APOE, TMEM18, TFAP2B) and pulse pressure (near FBN1, IGFBP3; known for implication in arterial stiffness processes).

We provide analytical and empirical evidence that cross-sectional genetic-by-age interaction can help pinpoint longitudinal-change effects, when cross-sectional data surpasses longitudinal sample size. Our findings shed light on the distinction between traits that are impacted by age-dependent genetic effects and those that are not.

The hypothalamus is a master regulator of energy balance in the body. First-order hypothalamic neurons localized in the arcuate nucleus sense systemic signals that indicate the energy stores in the body. Through distinct projections, arcuate nucleus neurons communicate with second-order neurons, which are mostly localized in the paraventricular nucleus and in the lateral hypothalamus. The signals then proceed to third- and fourth-order neurons that activate complex responses aimed at maintaining whole-body energy homeostasis. During the last 30 years, since the identification of leptin in 1994, there has been a great advance in the unveiling of the hypothalamic and extra-hypothalamic neuronal networks that control energy balance. This has contributed to the characterization of the mechanisms by which glucagon-like peptide-1 receptor agonists promote body mass reduction and has opened new windows of opportunity for the development of drugs to treat obesity. This review presents an overview of the mechanisms involved in the hypothalamic regulation of energy balance and discusses how advancements in this field are contributing to the development of new pharmacological strategies to treat obesity.

Background/Objectives: Childhood obesity is one of the most challenging contemporary public health problems. Children and adolescents with obesity experience multiple psychosocial difficulties, such as low self-esteem, depression, anxiety, and behavioral problems, which persist for a long time. The aim of the study was to assess the effect of a multidisciplinary personalized lifestyle intervention for depressive and anxiety symptoms, as evaluated by psychometric questionnaires, and their effect and association with cardiometabolic parameters in children and adolescents with overweight and obesity before and after the intervention. Methods: Six hundred and eleven (n = 611) children and adolescents (mean age ± SE: 10.39 ± 0.10 years; 51.5% females, 46.6% pubertal) were studied prospectively. Subjects were classified as being obese (50.2%), overweight (33.5%), or having a normal BMI (16.2%) according to IOTF criteria. All participants entered a 1-year lifestyle intervention program; laboratory investigations were obtained at the beginning and end of the study and two psychometric questionnaires were completed, the CDI and SCARED, which evaluate symptoms of depression and anxiety, respectively. Results: Following the lifestyle intervention, a significant decrease was noted in anxiety scores in all subjects and in depression scores in youth with obesity, as well as in adolescents with obesity, while females displayed a reduced response to the intervention. Insulin resistance and metabolic syndrome parameters, cortisol, PRL, and LH concentrations were positive predictors for depressive and anxiety symptoms. Conclusions: The implementation of a multidisciplinary personalized lifestyle intervention program in the management of childhood obesity is associated with a significant decrease in cardiometabolic and psychosocial comorbidities in children with and without excess adiposity. The improvement in mental health is likely mediated by an improvement in energy metabolism with subsequent improvement in neuroinflammation owing to lifestyle changes.

The global prevalence of obesity has more than doubled over the past four decades, currently affecting more than a billion individuals. Beyond its recognition as a high-risk condition that is causally linked to many chronic illnesses, obesity has been declared a disease per se that results in impaired quality of life and reduced life expectancy. Notably, two-thirds of obesity-related excess mortality is attributable to cardiovascular disease. Despite the increasingly appreciated link between obesity and a broad range of cardiovascular disease manifestations including atherosclerotic disease, heart failure, thromboembolic disease, arrhythmias, and sudden cardiac death, obesity has been underrecognized and sub-optimally addressed compared with other modifiable cardiovascular risk factors. In the view of major repercussions of the obesity epidemic on public health, attention has focused on population-based and personalized approaches to prevent excess weight gain and maintain a healthy body weight from early childhood and throughout adult life, as well as on comprehensive weight loss interventions for persons with established obesity. This clinical consensus statement by the European Society of Cardiology discusses current evidence on the epidemiology and aetiology of obesity; the interplay between obesity, cardiovascular risk factors and cardiac conditions; the clinical management of patients with cardiac disease and obesity; and weight loss strategies including lifestyle changes, interventional procedures, and anti-obesity medications with particular focus on their impact on cardiometabolic risk and cardiac outcomes. The document aims to raise awareness on obesity as a major risk factor and provide guidance for implementing evidence-based practices for its prevention and optimal management within the context of primary and secondary cardiovascular disease prevention.

In the present scenario, obesity is a challenging health problem and its prevalence along with comorbidities are on the rise around the world. Ingestion of fish becomes trendy in daily meals. Recent research has shown that marine fish oil (FO) (found in tuna, sardines, and mackerel) may offer an alternative method for reducing obesity and problems associated with it. Marine FO rich in long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) and long-chain omega-6 polyunsaturated fatty acids (LC n-6 PUFA) plays an important role in reducing abnormalities associated with the metabolic syndrome and has a variety of disease-fighting properties, including cardioprotective activity, anti-atherosclerotic, anti-obesity, anti-cancer, anti-inflammatory activity. Studies in rodents and humans have indicated that LC n-3 PUFA potentially elicit a number of effects which might be useful for reducing obesity, including suppression of appetite, improvements in circulation, enhanced fat oxidation, energy expenditure, and reduced fat deposition. This review discusses the interplay between inflammation and obesity, and their subsequent regulation via the beneficial role of marine FO, suggesting an alternative dietary strategy to ameliorate obesity and obesity-associated chronic diseases.

Obesity is a silent global pandemic. It is a condition associated with multiple risk factors and adverse outcomes that arise from the intertwined relationship between environmental factors and genetics. The genetic factors that cause phenotypic expression are variable. Monogenic obesity is a severe early-onset and rarer form of obesity, which presents with co-morbidities such as abnormal feeding behaviour. Monogenic obesity causes impaired weight regulation in the hypothalamus due to defects in the leptin-melanocortin signalling pathway. The emergence of a new therapeutic treatment, the melanocortin-4 receptor agonist setmelanotide (originally RM-493), has represented a breakthrough in the management of monogenic obesity and has raised hope in managing complex obesity. This review provides an overview of the setmelanotide trials that have taken place, as well as its mechanism of action, side effects and weight loss outcomes that led to its approval in the treatment of pro-opiomelanocortin (POMC) deficiency and proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency. It also explores setmelanotide's role in other genetic forms of obesity, such as hypothalamic obesity, Prader-Willi syndrome, Alström syndrome and other rare genetic conditions that are being investigated. This review aims to help to understand the pathophysiology of genetic obesity and aid in future treatment options for people with severe, complex genetic obesity.

Obesity is a chronic multi-system disease and major driver of type 2 diabetes and cardiometabolic disease. Nutritional interventions form the cornerstone of obesity and type 2 diabetes management. Some interventions such as Mediterranean diet can reduce incident cardiovascular disease, probably independently of weight loss. Weight loss of 5% or greater can improve many adiposity-related comorbidities. Although this can be achieved with lifestyle intervention, it is often difficult to sustain in the longer term due to adaptive endocrine changes. In recent years glucagon-like-peptide-1 receptor agonists (GLP-1RAs) have emerged as effective treatments for both type 2 diabetes and obesity. Newer GLP-1RAs can achieve average weight loss of 15% or greater and improve cardiometabolic health. There is heterogeneity in the weight loss response to GLP-1RAs, with a substantial number of patients unable to achieve 5% or greater weight. Weight loss, on average, is lower in older adults, male patients and people with type 2 diabetes. Mechanistic studies are needed to understand the aetiology of this variable response. Gastrointestinal side effects leading to medication discontinuation are a concern with GLP-1RA treatment, based on real-world data. With weight loss of 20% or higher with newer GLP-1RAs, nutritional deficiency and sarcopenia are also potential concerns. Lifestyle interventions that may potentially mitigate the side effects of GLP-1RA treatment and enhance weight loss are discussed here. The efficacy of such interventions awaits confirmation with well-designed randomized controlled trials.

Obesity causes significant morbidity and mortality globally. Research in the last three decades has delivered a step-change in our understanding of the fundamental mechanisms that regulate energy homeostasis, building on foundational discoveries in mouse models of metabolic disease. However, not all findings made in rodents have translated to humans, hampering drug discovery in this field. Here, we review how studies in mice and humans have informed our current framework for understanding energy homeostasis, discuss their challenges and limitations, and offer a perspective on how human studies may play an increasingly important role in the discovery of disease mechanisms and identification of therapeutic targets in the future.

Genes regulating body fat are shared with high fidelity by mice and humans, indicating that mouse knockout (KO) phenotyping might identify valuable antiobesity drug targets. Male Mrs2 magnesium transporter (Mrs2) KO mice were recently reported as thin when fed a high-fat diet (HFD). They also exhibited increased energy expenditure (EE)/body weight and had beiged adipocytes that, along with isolated hepatocytes, demonstrated increased oxygen consumption, suggesting that increased EE drove the thin phenotype. Here we provide our data on these and additional assays in Mrs2 KO mice. We generated Mrs2 KO mice by homologous recombination. HFD-fed male and female Mrs2 KO mice had significantly less body fat, measured by quantitative magnetic resonance, than wild-type (WT) littermates. HFD-fed Mrs2 KO mice did not demonstrate increased EE by indirect calorimetry and could not maintain body temperature at 4 °C, consistent with their decreased brown adipose tissue stores but despite increased beige white adipose tissue. Instead, when provided a choice between HFD and low-fat diet (LFD), Mrs2 KO mice showed a significant 15% decrease in total energy intake resulting from significantly lower HFD intake that offset numerically increased LFD intake. Food restriction studies performed using WT mice suggested that this decrease in energy intake could explain the loss of body fat. Oral glucose tolerance test studies revealed significantly improved insulin sensitivity in Mrs2 KO mice. We conclude that HFD-fed Mrs2 KO mice are thin with improved insulin sensitivity, and that this favorable metabolic phenotype is driven by hypophagia. Further evaluation is warranted to determine the suitability of MRS2 as a drug target for antiobesity therapeutics.

The number of individuals with obesity is at an all-time high, and the rate of obesity continues to climb each year. Obesity is a chronic disease with widespread effects throughout the body. Midwives and perinatal care providers need an understanding of the etiology, pathophysiology, and interventions for obesity. A review of evidence-based diet and lifestyle modifications, medications, and surgical procedures is presented.

Accelerated gastric emptying (GE) is a trait seen in obesity. Mutations in the hypothalamic leptin-melanocortin 4 receptor (Leptin-MC4R) pathway have been associated with obesity. We sought to investigate the association of leptin-MC4R pathway variants and GE in patients with obesity.

This is a cross-sectional study of patients with a history of severe obesity that were genotyped and completed a GE test by scintigraphy. We evaluated the percentage of GE (GE %) at 2 and 4 h between both groups using ANCOVA with weight and sex as covariates. We subdivide patients into carriers based on the location of the identified variants (i.e., upstream or downstream of the Leptin-MC4R pathway) and compared them with noncarriers using ANOVA. Results are presented as mean and standard deviation (± SD).

A total of 95 patients; nine carriers (67% females; 39.78 ± 12.33 years; BMI: 49.14 ± 12.96 kg/m2) and 86 noncarriers (87% female; 49.98 ± 13.74 years; BMI: 40.75 ± 6.29 kg/m2) were included. At 2 and 4 h, carriers had a delayed GE when compared noncarriers (p = 0.03 and p = 0.005, respectively). In carriers, when compared upstream carriers vs. downstream carriers vs. noncarriers by location there was a significant difference in GE among groups at 2 h and at 4 h (p = 0.02 and p = 0.01, respectively).

Carriers of heterozygous variants in the Leptin-MC4R pathway had a delayed GE compared to noncarriers. These findings point the important relationship between the Leptin-MC4R pathway and gastric motility.

Metabolic syndrome (MS) is defined by the outcome of interconnected metabolic factors that directly increase the prevalence of obesity and other metabolic diseases. Currently, obesity is considered one of the most relevant topics of discussion because an epidemic heave of the incidence of obesity in both developing and underdeveloped countries has been reached. According to the World Obesity Atlas 2023 report, 38% of the world population are presently either obese or overweight. One of the causes of obesity is an imbalance of energy intake and energy expenditure, where nutritional imbalance due to consumption of high-calorie fast foods play a pivotal role. The dynamic interactions among different risk factors of obesity are highly complex; however, the underpinnings of hyperglycemia and dyslipidemia for obesity incidence are recognized. Fast foods, primarily composed of soluble carbohydrates, non-nutritive artificial sweeteners, saturated fats, and complexes of macronutrients (protein-carbohydrate, starch-lipid, starch-lipid-protein) provide high metabolic calories. Several experimental studies have pointed out that dairy proteins and peptides may modulate the activities of risk factors of obesity. To justify the results precisely, peptides from dairy milk proteins were synthesized under in vitro conditions and their contributions to biomarkers of obesity were assessed. Comprehensive information about the impact of proteins and peptides from dairy milks on fast food-induced obesity is presented in this narrative review article.

Differences in the preoperative characteristics and weight loss outcomes after sleeve gastrectomy (SG) between patients with familial aggregation of obesity (FAO) and patients with sporadic obesity (SO) have not been elucidated.

To explore the impact of SG on weight loss and the alleviation of obesity-related comorbidities in individuals with FAO.

A total of 193 patients with obesity who underwent SG were selected. Patients with FAO/SO were matched 1:1 by propensity score matching and were categorized into 4 groups based on the number of first-degree relatives with obesity (1SO vs 1FAO, 2SO vs 2FAO). The baseline characteristics, weight loss outcomes, prevalence of obesity-related comorbidities and incidence of major surgery-related complications were compared between groups.

We defined FAO as the presence of two or more first-degree relatives with obesity. Patients with FAO did not initially show significant differences in baseline data, short-term postoperative weight loss, or obesity-related comorbidities when compared to patients with SO preoperatively. However, distinctions between the two groups became evident at the two-year mark, with statistically significant differences in both percentage of total weight loss (P = 0.006) and percentage of excess weight loss (P < 0.001). The FAO group exhibited weaker remission of type 2 diabetes mellitus (T2DM) (P = 0.031), hyperlipidemia (P = 0.012), and non-alcoholic fatty liver disease (NAFLD) (P = 0.003) as well as a lower incidence of acid reflux (P = 0.038).

FAO patients is associated with decreased mid-to-long-term weight loss outcomes; the alleviation of T2DM, hyperlipidemia and NAFLD; and decreased incidence of acid reflux postoperatively.

Obesity is a chronic condition which is identified by the buildup of excess body fat caused by a combination of various factors, including genetic predisposition and lifestyle choices. rs1137101 (A > G) polymorphism in the CHR1 domain of LEPR protein linked to different diseases including obesity. Nevertheless, the connection between this polymorphism and the likelihood of developing obesity has not been determined definitively. Therefore, a meta-analysis was conducted to assess the relationship between rs1137101 and the risk of obesity. The meta-analysis included all studies meeting pre-defined criteria, found through searching databases up until February 2023. A combined odds ratio with a 95% confidence interval was estimated as overall and in continent subgroups for homozygous, heterozygous, recessive, dominant and allelic models using the fixed or the random-effects model. The meta-analysis identified 39 eligible studies with cases and controls (6099 cases/6711 controls) in 38 articles under different ethnic backgrounds. The results indicated a significant relationship between rs1137101 and the likelihood of developing obesity in each of the genetic models [the homozygous model (GG vs. AA: 95% Confidence Interval = 1.12-1.73, Odds Ratio = 1.39, P value = 0.003); the heterozygous model (AG vs. AA: 95% Confidence Interval = 1.07-1.42, Odds Ratio = 1.23, P value = 0.005); the dominant model (AG/GG vs AA: 95% Confidence Interval = 1.10-1.49, Odds Ratio = 1.28, P value = 0.001); the recessive model (GG vs AA/AG: 95% Confidence Interval = 1.02-1.45, Odds Ratio = 1.21, P value = 0.03); and the allelic model (G vs A; 95% Confidence Interval = 1.07-1.33, Odds Ratio = 1.19, P value = 0.002)] tested. Additionally, with an FDR <0.05, all genotypic models demonstrated statistical significance. The association remained significant among subgroups of Asian and Caucasian populations, although analysis in some genetic models did not show a significant association. Begg's and Egger's tests did not show publication biases. In sensitivity analysis, one particular study was found to have an impact on the Recessive model's significance, but other models remained unaffected. The current meta-analysis found significant indications supporting the association between rs1137101 and obesity. To avail a deeper understanding of this association, future research should include large-scale studies conducted in diverse ethnic populations.

Canine obesity is a complex disease affected by genetic, endocrine and environmental factors. It is associated with reduced lifespan and many comorbidities. Prevalence differs by breed, with Labrador retrievers at high risk. Past data on how biological risk factors impact weight gain have been contradictory, possibly because they were obtained from genetically heterogeneous populations.

We investigated risk factors for canine obesity in a population of British Labrador retrievers (n = 521) with high-quality data on obesity, weight, owner-reported food motivation and related characteristics. We used linear regression to assess known and novel risk factors for obesity.

We found that neutering increased obesity in males (p < 0.001) but not females (p = 0.37). Older age was associated with obesity in female Labradors (p = 0.013) but not males (p = 0.49). We identified two new risk factors for obesity in Labrador retrievers: chocolate coat colour (p < 0.001) and high food motivation (p < 0.001).

Strategic recruitment to collect both obese and lean dogs means this cohort is not suitable for assessing obesity prevalence in UK Labrador retrievers.

Studying this genetically homogeneous population informs our knowledge of common risk factors for obesity and expands those relevant to Labrador retrievers.

Obesity rates are increasing almost everywhere in the world, although the pace and timing for this increase differ when populations from developed and developing countries are compared. The sharp and more recent increase in obesity rates in many Latin American countries is an example of that and results from regional characteristics that emerge from interactions between multiple factors. Aware of the complexity of enumerating these factors, we highlight eight main determinants (the physical environment, food exposure, economic and political interest, social inequity, limited access to scientific knowledge, culture, contextual behaviour and genetics) and discuss how they impact obesity rates in Latin American countries. We propose that initiatives aimed at understanding obesity and hampering obesity growth in Latin America should involve multidisciplinary, global approaches that consider these determinants to build more effective public policy and strategies, accounting for regional differences and disease complexity at the individual and systemic levels.

Obesity is a complex, chronic disease requiring a multidisciplinary approach to its management. In clinical practice, body mass index and waist-related measurements can be used for obesity screening. The estimated prevalence of obesity among adults worldwide is 12%. With the expected further increase in overall obesity prevalence, clinicians will increasingly be managing patients with obesity. Energy balance is regulated by a complex neurohumoral system that involves the central nervous system and circulating mediators, among which leptin is the most studied. The functioning of these systems is influenced by both genetic and environmental factors. Obesity generally occurs when a genetically predisposed individual lives in an obesogenic environment for a long period. Cardiologists are deeply involved in evaluating patients with obesity. Cardiovascular risk profile is one of the most important items to be quantified to understand the health risk due to obesity and the clinical benefit that a single patient can obtain with weight loss. At the individual level, appropriate patient involvement, the detection of potential obesity causes, and a multidisciplinary approach are tools that can improve clinical outcomes. In the near future, we will probably have new pharmacological tools at our disposal that will facilitate achieving and maintaining weight loss. However, pharmacological treatment alone cannot cure such a complex disease. The aim of this paper is to summarize some key points of this field, such as obesity definition and measurement tools, its epidemiology, the main mechanisms underlying energy homeostasis, health consequences of obesity with a focus on cardiovascular diseases and the obesity paradox.Level of evidence V: report of expert committees.

The study of adipose tissue has received considerable attention due to its importance not just in maintaining body energy homeostasis but also in playing a role in a number of other physiological processes. Beyond storing energy, adipose tissue is important in endocrine, immunological, and neuromodulatory functions, secreting hormones that participate in the regulation of energy homeostasis. An imbalance of these functions will generate structural and functional changes in the adipose tissue, favoring the secretion of deleterious adipocytokines that induce a pro-inflammatory state, allowing the development of metabolic and cardiovascular diseases and even some types of cancer. A common theme worldwide has been the development of professional guidelines for the control and treatment of obesity, with emphasis on hypocaloric diets and exercise. The aim of this review is to examine the pathophysiological mechanisms of obesity, considering the relationship among adipose tissue and two aspects that contribute positively or negatively to keeping a healthy body homeostasis, namely, exercise and noninfectious diseases. We conclude that the relationship of these aspects does not have homogeneous effects among individuals. Nevertheless, it is possible to establish some common mechanisms, like a decrease in pro-inflammatory markers in the case of exercise, and an increase in chronic inflammation in non-communicable diseases. An accurate diagnosis might consider the particular variables of a patient, namely their molecular profile and how it affects its metabolism, routines, and lifestyle; their underling health conditions; and probably even the constitution of their microbiome. We foresee that the development and accessibility of omics approaches and precision medicine will greatly improve the diagnosis, treatment, and successful outcomes for obese patients.

Obesity is a chronic, multifactorial, and morbid disease. In the United States, 69% of adults are overweight or have obesity, and the global prevalence of obesity is increasing. Obesity is influenced by genetic, neurologic, metabolic, enteric, and behavioral processes. It remains a key modifiable risk factor for many comorbid diseases, including cardiovascular disease, diabetes mellitus, and cancer. Whereas there are recent and significant advances in obesity therapy, including diets, lifestyle modifications, pharmacotherapies, endoscopic procedures, and bariatric surgeries, there is an immense need for a better understanding of the heterogeneity in the pathophysiologic process of obesity and outcomes. Here we review salient pathophysiologic mechanisms underlying the development and morbidity of obesity as well as pathophysiologically based classification systems that inform current obesity management and may inform improved and individualized management in the future.

A small fraction of patients diagnosed with obesity or diabetes mellitus has an underlying monogenic cause. Here, we constructed a targeted gene panel consisting of 83 genes reported to be causative for monogenic obesity or diabetes. We performed this panel in 481 patients to detect causative variants and compared these results with whole-exome sequencing (WES) data available for 146 of these patients. The coverage of targeted gene panel sequencing was significantly higher than that of WES. The diagnostic yield in patients sequenced by the panel was 32.9% with subsequent WES leading to three additional diagnoses with two novel genes. In total, 178 variants in 83 genes were detected in 146 patients by targeted sequencing. Three of the 178 variants were missed by WES, although the WES-only approach had a similar diagnostic yield. For the 335 samples only receiving targeted sequencing, the diagnostic yield was 32.2%. In conclusion, taking into account the lower costs, shorter turnaround time, and higher quality of data, targeted sequencing is a more effective screening method for monogenic obesity and diabetes compared to WES. Therefore, this approach could be routinely established and used as a first-tier test in clinical practice for specific patients.

Adiposity has gradually become a global public threat over the years with drastic increase in the attributable deaths and disability adjusted life years (DALYs). Given an increased metabolic risk among Asians as compared to Europeans for any given body mass index (BMI) and considering the differences in genetic architecture between them, the present review aims to summarize the findings from genome-wide scans for various adiposity indices and related anthropometric measures from Asian populations. The search for related studies, published till February 2022, were made on PubMed and GWAS Catalog using search strategy built with relevant keywords joined by Boolean operators. It was recorded that out of a total of 47 identified studies, maximum studies are from Korean population (n = 14), followed by Chinese (n = 7), and Japanese (n = 6). Nearly 200 loci have been identified for BMI, 660 for height, 16 for weight, 28 for circumferences (waist and hip), 32 for ratios (waist hip ratio [WHR] and thoracic hip ratio [THR]), 5 for body fat, 16 for obesity, and 28 for adiposity-related blood markers among Asians. It was observed that though, most of the loci were unique for each trait, there were 3 loci in common to BMI and WHR. Apart from validation of variants identified in European setting, there were many novel loci discovered in Asian populations. Notably, 125 novel loci form Asian studies have been reported for BMI, 47 for height, 5 for waist circumference, and 2 for adiponectin level to the existing knowledge of the genetic framework of adiposity and related measures. It is necessary to examine more advanced adiposity measures, specifically of relevance to abdominal adiposity, a major risk factor for cardiometabolic disorders among Asians. Moreover, in spite of being one continent, there is diversity among different ethnicities across Asia in terms of lifestyle, climate, geography, genetic structure and consequently the phenotypic manifestations. Hence, it is also important to consider ethnic specific studies for identifying and validating reliable genetic variants of adiposity measures among Asians.

Genetic disruption of key molecular components of the hypothalamic leptin-melanocortin pathway causes severe obesity in mice and humans. Physiological studies in people who carry these mutations have shown that the adipose tissue-derived hormone leptin primarily acts to defend against starvation. A lack of leptin causes an intense drive to eat and increases the rewarding properties of food, demonstrating that human appetite has a strong biological basis. Genetic studies in clinical- and population-based cohorts of people with obesity or thinness continue to provide new insights into the physiological mechanisms involved in weight regulation and identify molecular targets for weight loss therapy. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

Rare cases of paraneoplastic obesity in children suggest sporadic obesity might also arise from an adaptive immune cell-mediated mechanism. Since the hypothalamus is a central regulator of feeding behavior and energy expenditure, we quantified lymphocytic inflammation in this region in a cohort of obese and non-obese human post-mortem brains. We report that CD8-positive cytotoxic T-cells are increased in hypothalamic median eminence/arcuate nucleus (ME/Arc) and bed nucleus of the stria terminalis in 40% of obese compared to non-obese patients, but not in other hypothalamic nuclei or brain regions. CD8 T-cells were most abundant in individuals with concurrent obesity and diabetes. Markers of cytotoxic T-cell induced damage, activated caspase 3 and poly-ADP ribose, were also elevated in the ME/Arc of obese patients. To provoke CD8 cytotoxic T-cell infiltrates in ventromedial region of hypothalamus in mice we performed stereotactic injections of an adeno-associated virus expressing immunogenic green fluorescent protein or saline. AAV but not saline injections triggered hypothalamic CD8 T-cell infiltrates associated with a rapid weight gain in mice recapitulating the findings in human obesity. This is the first description of the neuropathology of human obesity and when combined with its reconstitution in a mouse model suggests adaptive immunity may drive as much as 40% of the human condition.

Obesity is a chronic disease that increases morbidity and mortality and adversely affects quality of life. The rapid rise of obesity has outpaced the development and deployment of effective therapeutic interventions, thereby creating a global health crisis. The presentation, complications, and response to obesity treatments vary, yet lifestyle modification, which is the foundational therapeutic intervention for obesity, is often "one size fits all." The concept of personalized medicine uses genetic and phenotypic information as a guide for disease prevention, diagnosis, and treatment and has been successfully applied in diseases such as cancer, but not in obesity. As we gain insight into the pathophysiologic mechanisms of obesity and its phenotypic expression, specific pathways can be targeted to yield a greater, more sustained therapeutic impact in an individual patient with obesity. A phenotype-based pharmacologic treatment approach utilizing objective measures to classify patients into predominant obesity mechanism groups resulted in greater weight loss (compared with a non-phenotype-based approach) in a recent study by Acosta and colleagues. In this review, we discuss the application of lifestyle modifications, behavior therapy and pharmacotherapy using the obesity phenotype-based approach as a framework.

There has been a major ongoing health impact of the COVID-19 pandemic on children's lives, including lifestyle and overall health. Enforcement of prevention measures, such as school closures and social distancing, has significantly affected children's daily routines and activities. This perspective manuscript aims to explore the rise in childhood obesity and its association with hypertension during pandemics. The COVID-19 pandemic has led to significant disruptions in children's routines, including reduced physical activity, increased sedentary behavior, and changes in dietary patterns. These factors, coupled with the psychological impact of the pandemic, have contributed to an alarming increase in childhood obesity rates. This paper has highlighted the concerning increase in childhood obesity and hypertension during pandemics. The disruptions caused by the COVID-19 pandemic, including reduced physical activity, increased sedentary behaviors, and changes in dietary patterns, have contributed to the rise in these health conditions. It is crucial to recognize the long-term consequences of childhood obesity and hypertension and the urgent need for a comprehensive approach to address them.

New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10-10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10-6). We conclude that people with 16p11.2 BP2-3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.

Obesity is a metabolic state generated by the expansion of adipose tissue. Adipose tissue expansion depends on the interplay between hyperplasia and hypertrophy, and is mainly regulated by a complex interaction between genetics and excess energy intake. However, the genetic regulation of adipose tissue expansion is yet to be fully understood. Obesity can be divided into common multifactorial/polygenic obesity and monogenic obesity, non-syndromic and syndromic. Several genes related to obesity were found through studies of monogenic non-syndromic obesity models. However, syndromic obesity, characterized by additional features other than obesity, suggesting a more global role of the mutant genes related to the syndrome and, thus, an additional peripheral influence on the development of obesity, were hardly studied to date in this regard. This review summarizes present knowledge regarding the hyperplasia and hypertrophy of adipocytes in common obesity. Additionally, we highlight the scarce research on syndromic obesity as a model for studying adipocyte hyperplasia and hypertrophy, focusing on Bardet-Biedl syndrome (BBS). BBS obesity involves central and peripheral mechanisms, with molecular and mechanistic alternation in adipocyte hyperplasia and hypertrophy. Thus, we argue that using syndromic obesity models, such as BBS, can further advance our knowledge regarding peripheral adipocyte regulation in obesity.

One lead genetic risk signal of obesity-the rs1421085 T>C variant within the FTO gene-is reported to be functional in vitro but lacks evidence at an organism level. Here we recapitulate the homologous human variant in mice with global and brown adipocyte-specific variant knock-in and reveal that mice carrying the C-allele show increased brown fat thermogenic capacity and resistance to high-fat diet-induced adiposity, whereas the obesity-related phenotypic changes are blunted at thermoneutrality. Both in vivo and in vitro data reveal that the C-allele in brown adipocytes enhances the transcription of the Fto gene, which is associated with stronger chromatin looping linking the enhancer region and Fto promoter. Moreover, FTO knockdown or inhibition effectively eliminates the increased thermogenic ability of brown adipocytes carrying the C-allele. Taken together, these findings identify rs1421085 T>C as a functional variant promoting brown fat thermogenesis.