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GNAS variants were recently described in 1% of patients not known to have pseudohypoparathyroidism/inactivating PTH/PTHrP signalling disorder 2 in the UK Genetics of Obesity Study. We describe a new missense GNAS variant, c.791A > C, p.(Asp264Thr), in a family with obesity, hyperphagia and mild PTH resistance. A 6-year-old female (body mass index +4.3 SD score [SDS], height +1.9 SDS) presented with hyperphagia and obesity from age 3 years. She had subtle brachydactyly, macrocephaly, and mildly delayed development. The 12-year-old brother (height +2.1 SDS, body mass index +2.9 SDS) had hyperphagia, obesity, mildly delayed development, and autism. He had subtle brachydactyly, as did the affected mother. We assessed the functional effect of the mutant, measuring cAMP production in cells transfected with wild type and mutant GNAS after ligand stimulation. Cells with the mutant GNAS showed impaired cAMP generation through melanocortin receptor 4, GH releasing hormone receptor, and PTH receptor. These cases demonstrate the clinical heterogeneity of monogenic disease, suggesting a need to test for PHP1A in children with obesity even without classical signs of PHP1A. [ABSTRACT FROM AUTHOR]

Bardet-Biedl Syndrome (BBS) is an autosomal recessive non-motile ciliopathy, caused by mutations in more than twenty genes. Their expression leads to the production of BBSome-building proteins or chaperon-like proteins supporting its structure. The prevalence of the disease is estimated at 1: 140,000 - 160,000 of life births. Its main clinical features are retinal dystrophy, polydactyly, obesity, cognitive impairment, hypogonadism, genitourinary malformations, and kidney disease. BBS is characterized by heterogeneous clinical manifestation and the variable onset of signs and symptoms. We present a case series of eight pediatric patients with BBS (6 boys and 2 girls) observed in one clinical center including two pairs of siblings. The patients' age varies between 2 to 13 years (average age of diagnosis: 22 months). At presentation kidney disorders were observed in seven patients, polydactyly in six patients' obesity, and psychomotor development delay in two patients. In two patients with kidney disorders, the genetic tests were ordered at the age of 1 and 6 months due to the presence of symptoms suggesting BBS and having an older sibling with the diagnosis of the syndrome. The mutations in the following genes were confirmed: BBS10, MKKS, BBS7/BBS10, BBS7, BBS9. All described patients developed symptoms related to the urinary system and kidney-function impairment. Other most common symptoms are polydactyly and obesity. In one patient the obesity class 3 was diagnosed with multiple metabolic disorders. In six patients the developmental delay was diagnosed. The retinopathy was observed only in one, the oldest patient. Despite having the same mutations (siblings) or having mutations in the same gene, the phenotypes of the patients are different. We aimed to addresses gaps in understanding BBS by comparing our data and existing literature through a narrative review. This research includes longitudinal data and explores genotype-phenotype correlations of children with BBS. BBS exhibits diverse clinical features and genetic mutations, making diagnosis challenging despite defined criteria. Same mutations can result in different phenotypes. Children with constellations of polydactyly and/or kidney disorders and/or early-onset obesity should be managed towards BBS. Early diagnosis is crucial for effective monitoring and intervention to manage the multisystemic dysfunctions associated with BBS. [ABSTRACT FROM AUTHOR]

Background and aims: Smokers tend to have a lower body weight than non‐smokers, but also more abdominal fat. It remains unclear whether or not the relationship between smoking and abdominal obesity is causal. Previous Mendelian randomization (MR) studies have investigated this relationship by relying upon a single genetic variant for smoking heaviness. This approach is sensitive to pleiotropic effects and may produce imprecise causal estimates. We aimed to estimate causality between smoking and abdominal obesity using multiple genetic instruments. Design: MR study using causal analysis using summary effect estimates (CAUSE) and latent heritable confounder MR (LHC‐MR) methods that instrument smoking using genome‐wide data, and also two‐sample MR (2SMR) methods. Setting: Genome‐wide association studies (GWAS) summary statistics from participants of European ancestry, obtained from the GWAS and Sequencing Consortium of Alcohol and Nicotine use (GSCAN), Genetic Investigation of Anthropometric Traits (GIANT) Consortium and the UK Biobank. Participants: We used GWAS results for smoking initiation (n = 1 232 091), life‐time smoking (n = 462 690) and smoking heaviness (n = 337 334) as exposure traits, and waist–hip ratio (WHR) and waist and hip circumferences (WC and HC) (n up to 697 734), with and without adjustment for body mass index (adjBMI), as outcome traits. Measurements: Smoking initiation, life‐time smoking, smoking heaviness, WHR, WC, HC, WHRadjBMI, WCadjBMI and HCadjBMI. Findings Both CAUSE and LHC‐MR indicated a positive causal effect of smoking initiation on WHR (0.13 [95% confidence interval (CI) = 0.10, 0.16 and 0.49 (0.41, 0.57), respectively] and WHRadjBMI (0.07 (0.03, 0.10) and 0.31 (0.26, 0.37). Similarly, they indicated a positive causal effect of life‐time smoking on WHR [0.35 (0.29, 0.41) and 0.44 (0.38, 0.51)] and WHRadjBMI [0.18 (0.13, 0.24) and 0.26 (0.20, 0.31)]. In follow‐up analyses, smoking particularly increased visceral fat. There was no evidence of a mediating role by cortisol or sex hormones. Conclusions: Smoking initiation and higher life‐time smoking may lead to increased abdominal fat distribution. The increase in abdominal fat due to smoking is characterized by an increase in visceral fat. Thus, efforts to prevent and cease smoking can have the added benefit of reducing abdominal fat. [ABSTRACT FROM AUTHOR]

Introduction: FTO gene belongs to the non-heme Fe (II) and 2 oxoglutarate-dependent dioxygenase superfamily. Polymorphisms within the first intron of the FTO gene have been examined across various populations, yielding disparate findings.The present study aimed to determine the impact of two intronic polymorphisms FTO 30685T/G (rs17817449) and -23525T/ A (rs9939609) on the risk of obesity in Punjab, India. Methods: Genotypic and biochemical analysis were done for 671 unrelated participants (obese = 333 and non-obese = 338) (age ≥ 18 years). Genotyping of the polymorphisms was done by PCR-RFLP method. However, 50% of the samples were sequenced by Sanger sequencing. Results: Both the FTO variants 30685 (TT vs GG: odds ratio (OR), 2.30; 95% confidence interval (CI), 1.39-3.79) and -23525 (TT vs AA: odds ratio (OR), 2.78; 95% confidence interval (CI), 1.37-5.64) showed substantial risk towards obesity by conferring it 2 times and 3 times, respectively. The analysis by logistic regression showed a significant association for both the variants 30685T/G (rs17817449) and -23525T/A (rs9939609) (OR = 2.29; 95%CI: 1.47-3.57) and (OR = 5.25; 95% CI: 2.68-10.28) under the recessive genetic model, respectively. The haplotype combination TA (30685; -23525) develops a 4 times risk for obesity (P = 0.0001). Among obese, the G allele of 30685T/G and A- allele of -23525T/A showed variance in Body mass index (BMI), waist circumference (WC), waist-to-height ratio(WHtR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and triglyceride(TG). Conclusion: The present investigation indicated that both the FTO 30685T/G (rs17817449) and -23525T/A (rs9939609) polymorphisms have a key impact on an individual's vulnerability to obesity in this population. [ABSTRACT FROM AUTHOR]

Hypertension is a leading risk factor for cardiovascular disease and is modulated by genetic variants. This study aimed to assess the effect of obesity genetic liability and physical activity on hypertension among European and African ancestry individuals within the UK Biobank (UKB). Participants were 230 115 individuals of European ancestry and 3239 individuals of African ancestry from UKB. Genetic liability for obesity were estimated using previously published data including genetic variants and effect sizes for body mass index (BMI), waist‐hip ratio (WHR) and waist circumference (WC) using Plink software. The outcome was defined as stage 2 hypertension (systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥90 mmHg, or the use of anti‐hypertensive medications). The association between obesity genetic liability and the outcome was assessed across categories of self‐reported physical activity using logistic regression. Among European ancestry participants, there was up to a 1.2 greater odds of hypertension in individuals with high genetic liability and low physical activity compared to individuals with low genetic liability and high physical activity (p < 0.001). In individuals engaging in low levels of physical activity compared with moderate/high physical activity, the effect of BMI genetic liability on hypertension was greater (pinteraction = 0.04). There was no evidence of an association between obesity genetic liability and hypertension in individuals of African ancestry in the whole sample or within separate physical activity groups (p > 0.05). This study suggests that higher physical activity levels are associated with lower odds of stage 2 hypertension among European ancestry individuals who carry high genetic liability for obesity. This cannot be inferred for individuals of African ancestry, possibly due to the low African ancestry sample size within the UKB. [ABSTRACT FROM AUTHOR]

Biologically based therapies such as GLP-1 agonists are used to treat patients with obesity. Medical-surgical nurses should be knowledgeable about GLP-1 agonists so they can educate patients on proper administration, monitoring, and prevention and management of potential adverse effects. [ABSTRACT FROM AUTHOR]

Background: The prevalence of obesity has been increasing worldwide. It has been reported that physiological and environmental factors such as diet, culture, physical activity, and genetics are the principal factors related to obesity. The fat mass and obesity-associated (FTO) gen variant (rs9939609: T>A) has been associated with class III obesity. The A variant has been correlated with anthropometric and metabolic alterations. Therefore, the purpose of this study was to analyze the association of the FTO rs9939609: T>A variant and environmental factors with clinical, anthropometric, and biochemical variables in subjects with class III obesity. Results: The A variant frequency was higher in the class III obesity group compared with the normal weight group (44% vs. 25%, p < 0.001). Subjects with the AA genotype had a higher body mass index (BMI) than those with the AT genotype (35.46 kg/m2 (31–39.8) vs. 26.91 kg/m2 (23.7–30), p = 0.005). Women with the AA genotype showed higher waist circumferences than the AT group (101.07 cm (90.9–111.1) vs. 85.45 cm (77–93.8) p = 0.047). The FTO A variant increases the risk by 3.54 times and physical inactivity increases the risk by 6.37 times for class III obesity. Conclusions: Our results suggest that among the studied variables, those most related to class III obesity were the FTO risk genotype (A allele) and physical inactivity. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the relationship between leptin and adiponectin gene polymorphisms, circulating levels of leptin and adiponectin, adiposity and clinical markers in patients with myelodysplastic syndrome (MDS). This cross-sectional study was conducted with 102 adults and elderly MDS patients and 102 age- and sex-matched controls. Clinical characteristics, co-morbidities, anthropometric data, laboratory evaluation and genetic analysis (polymorphisms −2548G > A/rs7799039 of the LEP gene and +276G > T/rs1501299 of the ADIPOQ gene) were investigated. Serum leptin was higher and adiponectin lower in MDS when compared with controls. There was a significant positive correlation between serum leptin levels and BMI (r = 0·264, P = 0·025), waist circumference (r = 0·235, P = 0·047), body fat percentage (BF %) (r = 0·373, P = 0·001) and the fat mass index (FMI) (r = 0·371, P < 0·001). A lower mean adiponectin was found among patients with high BF %, higher visceral adiposity index and metabolic syndrome. A significant association was found between the AA genotype (mutant) of the LEP polymorphism rs7799039 and male sex and blast excess (≥ 5 %). In addition, a significant association was observed between the TT genotype (mutant) of the ADIPOQ rs1501299 polymorphism and Fe overload. These results demonstrate the importance of a comprehensive and systematic evaluation in patients with MDS in order to identify and control negative factors not related to the disease at an early stage. [ABSTRACT FROM AUTHOR]

Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity. [ABSTRACT FROM AUTHOR]

Obesity is a significant health problem with a continuously increasing prevalence among children and adolescents that has become a modern pandemic during the last decades. Nowadays, the genetic contribution to obesity is well-established. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles, and meta-analyses regarding the genetics of obesity and current pharmacological treatment, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between December 2022 and December 2023. We used the terms "obesity", "genetics", "monogenic", "syndromic", "drugs", "autosomal dominant", "autosomal recessive", "leptin-melanocortin pathway", and "children" in different combinations. Recognizing the genetic background in obesity can enhance the effectiveness of treatment. During the last years, intense research in the field of obesity treatment has increased the number of available drugs. This review analyzes the main categories of syndromic and monogenic obesity discussing current data on genetic-based pharmacological treatment of genetic obesity and highlighting the necessity that cases of genetic obesity should follow specific, pharmacological treatment based on their genetic background. [ABSTRACT FROM AUTHOR]

Obesity is a common metabolic syndrome that causes a significant burden on individuals and society. Conventional therapies include lifestyle interventions, bariatric surgery, and pharmacological therapies, which are not effective and have a high risk of adverse events. Acupuncture is an effective alternative for obesity, it modulates the hypothalamus, sympathetic activity and parasympathetic activity, obesity-related hormones (leptin, ghrelin, insulin, and CCK), the brain-gut axis, inflammatory status, adipose tissue browning, muscle blood flow, hypoxia, and reactive oxygen species (ROS) to influence metabolism, eating behavior, motivation, cognition, and the reward system. However, hypothalamic regulation by acupuncture should be further demonstrated in human studies using novel techniques, such as functional MRI (fMRI), positron emission tomography (PET), electroencephalogram (EEG), and magnetoencephalography (MEG). Moreover, a longer follow-up phase of clinical trials is required to detect the long-term effects of acupuncture. Also, future studies should investigate the optimal acupuncture therapeutic option for obesity. This review aims to consolidate the recent improvements in the mechanism of acupuncture for obesity as well as discuss the future research prospects and potential of acupuncture for obesity. [ABSTRACT FROM AUTHOR]

Aim: This study aims to investigate the associations between genetic risk scores (GRS) for favourable and unfavourable adiposity and a wide range of adiposity‐related outcomes across diverse populations. Methods: We utilised previously identified variants associated with favourable (36 variants) and unfavourable (38 variants) adiposity to create GRS for each adiposity phenotype. We used summary statistics from 39 outcomes generated by the Pan‐UKB genome‐wide association studies Version 0.3, incorporating covariates such as age, sex and principal components in six populations: European (n = 420,531), African (6636), American (980), Central/South Asian (8876), East Asian (2709) and Middle Eastern (1599). Results: The favourable adiposity GRS was associated with a healthy metabolic profile, including lower risk of type 2 diabetes, lower liver enzyme levels, lower blood pressure, higher HDL‐cholesterol, lower triglycerides, higher apolipoprotein A, lower apolipoprotein B, higher testosterone, lower calcium and lower insulin‐like growth factor 1 generally consistently across all the populations. In contrast, the unfavourable adiposity GRS was associated with an adverse metabolic profile, including higher risk of type 2 diabetes, higher random glucose levels, higher HbA1c, lower HDL‐cholesterol, higher triglycerides, higher liver enzyme levels, lower testosterone, and higher C‐reactive protein generally consistently across all the populations. Conclusion: The study provides evidence that the genetic scores associated with favourable and unfavourable adiposity have consistent effects on metabolic profiles and disease risk across diverse ethnic groups. These findings deepen our understanding of distinct adiposity subtypes and their impact on metabolic health. [ABSTRACT FROM AUTHOR]

In recent years, obesity is a growing pandemic in the world and has likely contributed to increasing the incidence of obesity-related diseases. Fat mass and obesity-associated gene (FTO) is the first gene discovered which has a close connection with fat. Recent studies suggested that FTO gene has played an important role in the molecular mechanisms of many diseases. Obesity is considered to be a hereditary disease and can evoke many kinds of diseases, including polycystic ovary syndrome (PCOS), type 2 diabetes mellitus (T2DM), cancer, etc., whose exact possible molecular mechanisms responsible for the effect of FTO on obesity and obesity-related diseases remain largely unknown. In this review, we comprehensively discuss the correlation between FTO gene and obesity, cancer, PCOS, T2DM, as well as the molecular mechanism involved in these diseases. [ABSTRACT FROM AUTHOR]

Background: Obesity is highly influenced by heritability and variant effects. While previous genome-wide association studies (GWASs) have successfully identified numerous genetic loci associated with obesity-related traits [body mass index (BMI) and waist-to-hip ratio (WHR)], most causal variants remain unidentified. The high degree of linkage disequilibrium (LD) throughout the genome makes it extremely difficult to distinguish the GWAS-associated SNPs that exert a true biological effect. Objective: This study was to identify the potential causal variants having a biological effect on obesity-related traits. Methods: We used Probabilistic Annotation INTegratOR, a Bayesian fine-mapping method, which incorporated genetic association data (GWAS summary statistics), LD structure, and functional annotations to calculate a posterior probability of causality for SNPs across all loci of interest. Moreover, we performed gene expression analysis using the available public transcriptomic data to validate the corresponding genes of the potential causal SNPs partially. Results: We identified 96 SNPs for BMI and 43 SNPs for WHR with a high posterior probability of causality (> 99%), including 49 BMI SNPs and 24 WHR SNPs which did not reach genome-wide significance in the original GWAS. Finally, we partially validated some genes corresponding to the potential causal SNPs. Conclusion: Using a statistical fine-mapping approach, we identified a set of potential causal variants to be prioritized for future functional validation and also detected some novel trait-associated variants. These results provided novel insight into our understanding of the genetics of obesity and also demonstrated that fine mapping may improve upon the results identified by the original GWASs. [ABSTRACT FROM AUTHOR]

This study provides a thorough comparison of the plasma metabolome of two rabbit lines divergently selected for intramuscular fat content (IMF). The divergent selection led to a correlated response in the overall adiposity, turning these lines into a valuable animal material to study also the genetics of obesity. Over 900 metabolites were detected, and the adjustment of multivariate models, both discriminant and linear, allowed to identify 322 with differential abundances between lines, which also adjusted linearly to the IMF content. The most affected pathways were those of lipids and amino acids, with differences between lines ranging from 0.23 to 6.04 standard deviations, revealing a limited capacity of the low-IMF line to obtain energy from lipids, and a greater branched-chain amino acids catabolism in the high-IMF line related to its increased IMF content. Additionally, changes in metabolites derived from microbial activity supported its relevant role in the lipid deposition. Future research will focus on the analysis of the metabolomic profile of the cecum content, and on the integration of the several -omics datasets available for these lines, to help disentangle the host and microbiome biological mechanisms involved in the IMF deposition. Comprehensive metabolomic profiling of plasma samples from two rabbit lines that were divergently selected for intramuscular fat content highlights the contribution of host genetics and microbial-derived metabolites to obesity or lipid deposition. [ABSTRACT FROM AUTHOR]

Over the past 50 years, the number of overweight/obese people increased significantly, making obesity a global public health challenge. Apart from rare monogenic forms, obesity is a multifactorial disease, most likely resulting from a concerted interaction of genetic, epigenetic and environmental factors. Although recent studies opened new avenues in elucidating the complex genetics behind obesity, the biological mechanisms contributing to individual's risk to become obese are not yet fully understood. Non-genetic factors such as eating behaviour or physical activity are strong contributing factors for the onset of obesity. These factors may interact with genetic predispositions most likely via epigenetic mechanisms. Epigenome-wide association studies or methylomewide association studies are measuring DNA methylation at single CpGs across thousands of genes and capture associations to obesity phenotypes such as BMI. However, they only represent a snapshot in the complex biological network and cannot distinguish between causes and consequences. Intervention studies are therefore a suitable method to control for confounding factors and to avoid possible sources of bias. In particular, intervention studies documenting changes in obesity-associated epigenetic markers during lifestyle driven weight loss, make an important contribution to a better understanding of epigenetic reprogramming in obesity. To investigate the impact of lifestyle in obesity state specific DNA methylation, especially concerning the development of new strategies for prevention and individual therapy, we reviewed 19 most recent human intervention studies. In summary, this review highlights the huge potential of targeted interventions to alter disease-associated epigenetic patterns. However, there is an urgent need for further robust and larger studies to identify the specific DNA methylation biomarkers which influence obesity. [ABSTRACT FROM AUTHOR]

Background: Some persons are genetically resistant to obesity, but only a few studies have evaluated thinness genes for preventing obesity. We aimed to investigate the association of polygenic variants with being underweight and their interaction with the lifestyles of middle‐aged and elderly persons and identify potential new genetic approaches for managing body weight. Methods: In total, 58,701 participants aged 40–77 years were recruited from urban hospitals in Korea. Underweight (case) was defined as body mass index (BMI) < 18.5 kg m2 (n = 991) and normal weight (control, n = 21,921) was defined as 18.5 ≤ BMI < 23 kg m2. A genome‐wide association study was run to identify thinness‐related single nucleotide polymorphisms (SNPs) after adjustment for compound factors using Gplink. The generalised multifactor dimensionality reduction program was used to identify the genetic variants with SNP–SNP interactions. The polygenic risk score (PRS) was calculated by summing up the number of risk alleles in each SNP and classifying them into low‐, medium‐ and high‐PRS. Results: The best model included the ANK2_rs7656666, CAST_rs28042, SLC1A3_rs928431867, CHST12_rs2906173, ALOX5_rs1051713, RGS6_rs17180754, ST8SIA5_rs79491311 and DCC_rs35721894 alleles. The participants with high‐PRS had a lower BMI (p < 0.0001) than those with low‐PRS and were 3.834 (2.58–5.70) times more likely to be underweight after multivariate adjustment (p < 0.001). The selected SNPs were correlated with each other and highly expressed in brain‐related genes. The genes with minor alleles of CAST_rs28042 and CHST12_rs2906173 exhibited a higher expression frequency in brain‐related tissues. PRS had significant interactions with protein, sodium, indigestible carbohydrates, calcium intake and exercise (p < 0.05), influencing the underweight state. People with a high‐PRS were more underweight than those with low‐PRS under high protein, sodium, high calcium, low indigestible carbohydrate intake and low exercise by 3.75, 3.88, 7.05, 3.18 and 3.80 times, respectively (p < 0.0001). Conclusions: In conclusion, adults having a high‐PRS were significantly correlated with being underweight, especially in combination with a particular nutritional status. These results show the potential for thinness genes to be applied to personalised nutrition for preventing obesity through targeted gene therapy. Highlights: There is less research on understanding the role of genetic mutations in maintaining underweight. The present study found that high‐risk scores of thinness‐related polygenic variants (PRS) were positively associated with being underweight by 3.83 times. PRS interacted with environmental factors, including protein, indigestible carbohydrates, sodium and calcium intake, as well as physical activity. The study clearly suggests that the discovery of single nucleotide polymorphism (SNP)–environment interactions by using PRS was notable for its influence on the state of being underweight. Therapies targeting these genes and the SNPs of PRS could help scientists prevent obesity and manage weight in the future. [ABSTRACT FROM AUTHOR]

Background/Aim: Obesity is associated with the structural and functional disorders related to the molecules of the tissues, cells, and membranes. This study aimed to examine the alterations in the secretion of inflammatory cytokines and metabolic factors and structural changes in inguinal (IF) and gonadal (GF) adipose tissues at the molecular level. Materials and Methods: The IF and GF tissues of Berlin Fat Mouse Inbred (BFMI) lines namely BFMI852, BFMI856, BFMI860, BFMI861 obese and DBAJ control mouse lines were used for mRNA expression and Attenuated Total Reflection - Fourier Transform Infrared Spectroscopy (ATR-FTIR) studies. The mRNA levels of inflammatory cytokines including leptin, interleukin 6 (IL-6), tumor necrosis factor-alpha (Tnf-a), and insulin-like growth factor-1 (Igf-1), and peroxisome proliferator-activated receptor gamma 2 (Pparγ-2), were investigated using quantitative reverse transcriptase real-time PCR (qRT-PCR). Infrared spectroscopy does not provide information about specific proteins, instead, it gives information about overall (total) proteins, which is called global information. Therefore, in the current study, adequate information about secondary structures of adipose tissues proteins was obtained using artificial neural network (ANN) and secondary derivative-vector normalization methods based on the spectral profiles. Results: According to the mRNA expression studies, high leptin resistance was found in all BFMI lines. Differences were observed in the levels of measured factors except for Igf-1 among BFMI lines. Protein secondary structure studies showed an increase in random coil contents, especially for BFMI860, which indicates denaturation of the proteins. Conclusion: Among the spontaneous obese BFMI mouse lines, the BFMI860 line is the most suitable for obesity studies. Obesity-induced effect on the adipose tissues varies considerably with location, type of adipose tissue, and animal line. [ABSTRACT FROM AUTHOR]

Background: People with severe mental illness (SMI) have an elevated risk of obesity but the causes and mechanisms are unclear. We explored the familial association between parental SMI and body mass index (BMI) in middle-aged offspring. Our objective was to determine if the offspring of either parent with SMI have an increased risk for obesity. Methods: The Northern Finland Birth Cohort 1966 is a cohort study of offspring with expected date of birth in 1966. The data include originally 12 068 mothers and 12 231 children from the provinces of Lapland and Oulu in Finland. The final study sample included 5050 middle-aged offspring. Parental SMI was used as exposure in the study. BMI measured at the age of 46 years was used as a primary outcome. Results: Risk for obesity was elevated in the offspring of mothers with SMI [overweight: adjusted odds ratio (OR) 1.93 (1.29–2.90), obese class I: 1.97 (1.20–3.25), obese classes II–III: 2.98 (1.67–5.33)]. For the offspring of either parent with SMI, statistically significant results were found in obese class I and obese classes II–III [overweight: adjusted OR 1.21 (0.94–1.54), obese class I: 1.52 (1.03–1.08), obese classes II–III: 1.53 (1.01–2.32)]. Conclusions: We found an elevated risk of obesity in the middle-aged offspring of either parent with SMI, especially in the offspring of mothers with SMI. Thus, there might be a common familial pathway leading to the co-occurrence of obesity and SMI. [ABSTRACT FROM AUTHOR]

Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities, including monogenic and syndromic obesities, are rare and complex neuro-endocrine pathologies where the genetic contribution is predominant. Severe and early-onset obesity with eating disorders associated with frequent comorbidities make these diseases challenging. Their current estimated prevalence of 5-10% in severely obese children is probably underestimated due to the limited access to genetic diagnosis. A central alteration of hypothalamic regulation of weight implies that the leptin-melanocortin pathway is responsible for the symptoms. The management of genetic obesity has so far been only based, above all, on lifestyle intervention, especially regarding nutrition and physical activity. New therapeutic options have emerged in the last years for these patients, raising great hope to manage their complex situation and improve quality of life. Implementation of genetic diagnosis in clinical practice is thus of paramount importance to allow individualized care. This review describes the current clinical management of genetic obesity and the evidence on which it is based. Some insights will also be provided into new therapies under evaluation. [ABSTRACT FROM AUTHOR]

The objective was to determine how miRNA expression levels related to obesity and weight loss interacted, to forecast how much weight patients could lose after surgery, and to maximize the advantages of a scheduled procedure. 17 patients who planned laparoscopic sleeve gastrectomy were included. Demographic variables, comorbid conditions, and postoperative excess weight loss rates (EWL%) were evaluated. Both intraoperative adipose tissue samples and blood samples were taken. The gene expression levels of the miRNAs (miR27b-3p, miR122-5p, and miR223-3p) linked to diabetes and obesity were investigated. Mean body mass index was 49.17.6 kg/m2. Six individuals had diabetes mellitus, and their mean blood sugar and HbA1c levels were 133±59.4 mg/dl and 6.4±1.3%, respectively. All preoperative groups had considerably higher levels of miR223-3p expression, it was discovered. Blood samples taken before and after surgery showed considerably higher levels of miR223-3p gene expression than those of miR27b-3p and miR122-5p. Additionally, it was discovered that in individuals with diabetes mellitus, miR122-5p gene expression in fatty tissue was lower than that of miR223-3p and miR27b-3p. MiR223-3p expression has been linked to morbidly obese patients, particularly those with EWLs of 50% and above. After bariatric surgery, the miR223-3p gene may be utilized as a potential biomarker to predict a patient's capacity to lose weight. It is possible to identify patients who will not benefit from surgery and decide to perform a different kind of operation on them. However, additional research involving more patients, additional miRNAs, and various bariatric surgery techniques is required. [ABSTRACT FROM AUTHOR]

Since the beginning of their production, in the 1930s, phthalates have been widely used in the plastics industry to provide durability and elasticity to polymers that would otherwise be rigid, or as solvents in hygiene and cosmetic products. Taking into account their wide range of applications, it is easy to understand why their use has been increasing over the years, making them ubiquitous in the environment. This way, all living organisms are easily exposed to these compounds, which have already been classified as endocrine disruptor compounds (EDC), affecting hormone homeostasis. Along with this increase in phthalate-containing products, the incidence of several metabolic diseases has also been rising, namely diabetes. That said, and considering that factors such as obesity and genetics are not enough to explain this substantial increase, it has been proposed that the exposure to environmental contaminants may also be a risk factor for diabetes. Thus, the aim of this work is to review whether there is an association between the exposure to phthalates and the development of the several forms of diabetes mellitus, during pregnancy, childhood, and adulthood. [ABSTRACT FROM AUTHOR]

Background The co-presentation of severe obesity (SO) and global developmental delay (GDD) in Canadian preschool children has not been examined. However, SO and GDD may require syndromic diagnoses and unique management considerations. Objectives To determine (1) minimum incidence; (2) age of onset and risk factors; and (3) health care utilization for co-presenting SO and GDD. Methods Through the Canadian Paediatric Surveillance Program (CPSP), a monthly form was distributed to participants from February 2018 to January 2020 asking for reports of new cases of SO and GDD among children ≤5 years of age. We performed descriptive statistics for quantitative questions and qualitative content analysis for open-ended questions. Results Forty-seven cases (64% male; 51% white; mean age: 3.5 ± 1.2 years) were included. Age of first weight concern was 2.5 ± 1.3 years and age of GDD diagnosis was 2.7 ± 1.4 years. Minimum incidence of SO and GDD was 3.3 cases per 100,000 for ≤5 years of age per year. Identified problems included school and/or behavioural problems (n = 17; 36%), snoring (n = 14; 30%), and asthma/recurrent wheeze (n = 10; 21%). Mothers of 32% of cases (n = 15) had obesity and 21% of cases (n = 10) received neonatal intensive care. Microarray was ordered for 57% (n = 27) of children. A variety of clinicians and services were accessed. As reported by CPSP participants, challenges faced by families and health service access were barriers to care. Conclusion Children with SO and GDD have multiple comorbidities, and require early identification and referral to appropriate services. These cases may also benefit from additional testing to rule out known genetic obesity syndromes. [ABSTRACT FROM AUTHOR]

Purpose: Paradoxes have been found in obesity, including individuals with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO), and diet may be one of the reasons for the creation of these metabolic phenotypes. Hence, the purpose of the present study was to investigate the association of the Mediterranean-DASH intervention for neurodegenerative delay (MIND) diet with metabolically unhealthy overweight/obesity (MUHOW/O) phenotypes. Methods: In this cross-sectional study, 229 overweight and obese women (body mass index (BMI) ≥ 25 kg/m2) aged 18–48 years were examined. Anthropometric measures and biochemical parameters were collected from all participants. The body composition of each participant was assessed using a bioelectrical impedance analyzer (BIA). The MIND diet score was determined based on 15 components using a valid and reliable food frequency questionnaire (FFQ) containing 147 items. Karelis criteria was used to determine metabolically healthy/unhealthy phenotype (MH/MUH). Results: Among the participants, 72.5% of individuals were identified as MUH and 27.5% as MH, with a mean ± standard deviation (SD) age of 36.16 (8.33) years. The results of our analysis showed that after controlling for age, energy intake, BMI, and physical activity, there was no significant association observed between overweight/obesity phenotypes with tertile 2 (T2) (OR: 2.01, 95% CI: 0.86–4.17, P-value = 0.10), T3 (OR: 1.89, 95% CI: 0.86–4.17, P-value = 0.11) of MIND score, and only the odds of MUH relative to MH with a marginal significant decreasing trend was observed from the second to the third tertile (1.89 vs. 2.01) (P − trend = 0.06). Also, after additional adjustment for marital status, the nonsignificant association between overweight/obesity phenotypes with tertile 2 (T2) (OR: 2.13, 95% CI: 0.89−5.10, P-value = 0.08), T3 (OR: 1.87, 95% CI: 0.83−4.23, P-value = 0.12) of MIND score remained, and the odds of MUH relative to MH with a significant decreasing trend was observed with increasing tertiles (P-trend = 0.04). Conclusions: In conclusion, no significant associations were found between adherence to MIND diet with MUH, and only a significant downward trend in the odds of MUH was observed with increasing tertiles. We suggest further studies in this field. [ABSTRACT FROM AUTHOR]

Obesity, a chronic metabolic disorder caused by an energy imbalance, has been increasingly prevalent and poses a global health concern. The multifactorial etiology of obesity includes genetics factors, high-fat diet, gut microbiota, and other factors. Among these factors, the implication of gut microbiota in the pathogenesis of obesity has been prominently acknowledged. This study endeavors to investigate the potential contribution of gut microbiota to the development of high-fat diet induced obesity, as well as the current state of probiotic intervention therapy research, in order to provide novel insights for the prevention and management of obesity. [ABSTRACT FROM AUTHOR]

Different phenotypes of obesity are each related with different complications and comorbidities. We hypothesized that suboptimal vitamin D status is directly associated with an unhealthy metabolic status, especially if allied with obesity. This cross-sectional study was performed in the framework of the National Food and Nutrition Surveillance. Overall, 1098 men and women participated in this study. In addition to height and weight, serum concentrations of 25-hydroxyvitamin D (25(OH)D) and glycemic and lipidemic status were evaluated. Then participants were classified into 4 groups based on body mass index and lipidemic and glycemic profile status, as follows: hyperglycemic-dyslipidemic obese (HDO), hyperglycemic-dyslipidemic nonobese (HDNO), normoglycemic-normolipidemic obese (NNO), and normoglycemic-normolipidemic nonobese (NNNO). In this study, 31.6% of participants were classified as HDO, 7.5% as HDNO, 34.5% as NNO, and 26.4% as NNNO. The frequency of suboptimal vitamin D status was more prevalent in HDO (81.8%) than in other phenotypes (HDNO, 80%; NNO, 77.6%; NNNO, 73.8%; P =.015). In the multivariate model, suboptimal vitamin D status significantly increased the odds of being NNO (odds ratio [OR], 1.28; 95% CI, 0.84-1.95), HDNO (OR, 1.48; 95% CI, 0.77-2.83), and HDO (OR, 1.73; 95% CI, 1.11-2.7) compared with the NNNO group. Likewise, in multivariate model, per each unit (ng/mL) increment in 25(OH)D concentration, the odds of HDNO and HDO decreased significantly by 4% (OR, 0.96; 95% CI, 0.94-0.98) and 7% (OR, 0.93; 95% CI, 0.92-0.95), respectively. The results of the study showed a significant relationship between serum 25(OH)D concentrations and metabolic obesity phenotypes; these data confirm the association between suboptimal vitamin D status and metabolic complications, especially in obese individuals. [Display omitted] During exposure to sunlight, 7-dehydrocholesterol in the skin absorbs UV B radiation and is converted to previtamin D3. Vitamin D, after being activated in the liver and kidney, exerts its protective effects against metabolic disorders. Hypovitaminosis D is associated with metabolic complications such as dyslipidemia and diabetes, especially in obese people. 25(OH)D, 25 hydroxyvitamin D; 1,25(OH) 2 D, 1, 25 Di hydroxyvitamin D. [ABSTRACT FROM AUTHOR]

The main aim of this study was to evaluate the effects of Na intake and cardiorespiratory fitness (CRF) on body composition. The study was also intended to assess whether Na intake and/or CRF mediate the genetic susceptibility to obesity. Analyses were performed on a sample of 526 adult participants from the Quebec Family Study for whom a complete data set was available for nutrient and energy intake, CRF and body composition variables. The effects of Na, CRF and their interaction were analysed by comparing sex-specific tertiles using general linear mixed models. In both males and females, we observed a significant effect of Na intake and CRF on all body composition variables. However, in females only, we found that the effect of Na intake on body composition variables varies according to CRF level such that high Na intake was associated with increased body fatness, but only in females with low CRF. This interaction effect remained significant after statistical adjustment for total sugar, fat and energy intake. Using mediation analysis, we also found Na intake and CRF to be significant mediators of the relationship between a polygenic risk score of obesity based on > 500 000 genetic variants and BMI or waist circumference. In conclusion, the current study shows that Na intake influences body composition via mechanisms that interact with aerobic fitness, especially in females. Furthermore, both Na intake and CRF seem to be involved in the expression of the genetic susceptibility to obesity. [ABSTRACT FROM AUTHOR]

Background. Over the last few years, the importance of leptin in energy metabolism has been extensively studied in both animal models and in humans. Very few results are available on the association between human leptin gene (LEP) variants and obesity traits in India. We designed this study to analyse the polymorphisms in human leptin gene and the association of sequence variants with obesity among the population in Kerala, South India. Methods. In this case-control design of 148 study participants, data were collected on socioeconomic aspects and anthropometric measurements. Plasma glucose, insulin, leptin, and lipid profile were measured. Genotyping was done by automated DNA sequencing. Results. The common Single Nucleotide Polymorphism (SNP) of 5′-UTR of LEP − 2548G/A was found to be present in the study population with "A" variant as dominant allele. A novel synonymous mutation Thr5Thr of exon 2 of LEP was identified in heterozygous form in one subject with morbid obesity with hyperleptinemia. A novel missense mutation Phe17Leu was observed in two subjects with obesity in heterozygous condition. A novel missense mutation Lys36Arg in exon 2 of LEP was observed in one subject with abdominal obesity and decreased serum leptin level. Conclusion. LEP − 2548G/A at 5′-untranslated region was found to be common with the mutant "A" variant in the study population. SNPs of exons in LEP were found to be rare but associated with morbid obesity and altered levels of serum leptin in the study population in Kerala, India. [ABSTRACT FROM AUTHOR]

The American Medical Association recognized obesity as a disease in 2013. Obesity is influenced by genetic, environmental, physiologic, behavioral, and sleep factors and is associated with approximately 200 health conditions. Assessed using body mass index, body composition, and evaluation of weight-related complications, obesity is treated with lifestyle interventions, anti-obesity medications, and metabolic and bariatric surgery. The age-adjusted prevalence of overweight and obesity in US adults has increased substantially in the 21st century, from an estimated 56% in 1988-1994 to approximately 73.1% in 2017-2018. Nevertheless, there are substantial barriers to successful obesity treatment in the United States, including inadequate treatment coverage; a lack of acceptance by providers, patients, and employers that obesity is a disease; the perception that treatment is ineffective; and the belief that obesity is a behavioral concern related to a lack of willpower. Obesity is a serious, chronic, relapsing, and treatable disease associated with many related conditions; it requires long-term medical management and multimodal care strategies. [ABSTRACT FROM AUTHOR]

Globally, more than 1.9 billion adults are overweight. Thus, obesity is a serious public health issue. Moreover, obesity is a major risk factor for diabetes mellitus, coronary heart disease, and cardiovascular disease. Recently, GWAS examining obesity and body mass index (BMI) have increasingly unveiled many aspects of the genetic architecture of obesity and BMI. Information on genome-wide genetic variants has been used to estimate the genome-wide polygenic score (GPS) for a personalized prediction of obesity. However, the prediction power of GPS is affected by various factors, including the unequal variance in the distribution of a phenotype, known as heteroscedasticity. Here, we calculated a GPS for BMI using LDpred2, which was based on the BMI GWAS summary statistics from a European meta-analysis. Then, we tested the GPS in 354,761 European samples from the UK Biobank and found an effective prediction power of the GPS on BMI. To study a change in the variance of BMI, we investigated the heteroscedasticity of BMI across the GPS via graphical and statistical methods. We also studied the homoscedastic samples for BMI compared to the heteroscedastic sample, randomly selecting samples with various standard deviations of BMI residuals. Further, we examined the effect of the genetic interaction of GPS with environment (GPS×E) on the heteroscedasticity of BMI. We observed the changing variance (i.e., heteroscedasticity) of BMI along the GPS. The heteroscedasticity of BMI was confirmed by both the Breusch-Pagan test and the Score test. Compared to the heteroscedastic sample, the homoscedastic samples from small standard deviation of BMI residuals showed a decreased heteroscedasticity and an improved prediction accuracy, suggesting a quantitatively negative correlation between the phenotypic heteroscedasticity and the prediction accuracy of GPS. To further test the effects of the GPS×E on heteroscedasticity, first we tested the genetic interactions of the GPS with 21 environments and found 8 significant GPS×E interactions on BMI. However, the heteroscedasticity of BMI was not ameliorated after adjusting for the GPS×E interactions. Taken together, our findings suggest that the heteroscedasticity of BMI exists along the GPS and is not affected by the GPS×E interaction. [ABSTRACT FROM AUTHOR]

Dietary intake may interact with gene variants and modulate inflammatory status. This study aimed to investigate the combined effect of fat mass and obesity-associated rs9930501, rs9930506, and rs9932754 and beta-2 adrenergic receptor rs1042713 on C-reactive protein (CRP) concentrations using polygenic risk scores (PRS), and modulatory effect of dietary nutrients on these associations. We hypothesized that higher protein intake is associated with lower inflammatory status in individuals genetically predisposed to obesity. PRS was computed as the weighted sum of the risk alleles possessed and stratified into first (0-0.64), second (0.65-3.59), and third (3.60-8.18) tertiles. A total of 128 overweight and obese Malaysian adults were dichotomized into groups of low and elevated inflammatory status (CRP concentrations ≤3 and >3 mg/L, respectively). One-half of the study participants (51%) were found to have elevated inflammatory status. Second- and third-tertile PRS were significantly associated with increased odds of elevated inflammatory status, 7.56 (95% confidence interval [CI], 1.98-28.80; adjusted P =.003) and 3.87 (95% CI, 1.10-13.60; adjusted P =.035), respectively. Individuals in the third-tertile PRS had significantly lower CRP concentrations (4.61 ± 1.3 mg/L vs 9.60 ± 2.6 mg/L, P =.019) when consuming ≥14% energy from protein (with an average of 18.0% ± 2.4%, 43.0% ± 7.7%, and 39.0% ± 8.0% energy from protein, carbohydrate, and fat per day). In conclusion, third-tertile PRS was significantly associated with increased odds of elevated CRP; higher protein intake may alleviate inflammatory status and reduce CRP concentrations systemically in those individuals. Serum concentrations of C-reactive protein were significantly lower among overweight and obese Malaysian adults in the highest tertile polygenic risk scores, consuming ≥14% energy from protein per day compared with those consuming <14% energy from protein per day. This finding suggests that dietary protein according to the current findings may lower C-reactive protein concentrations of overweight and obese adults with high polygenic risk scores. [Display omitted] [ABSTRACT FROM AUTHOR]

Keywords: melanocortin 4 receptor; MC4R; stop mutation; PTC; translational readthrough; G418 EN melanocortin 4 receptor MC4R stop mutation PTC translational readthrough G418 1793 17 11/17/22 20221101 NES 221101 1. On the other hand, the W258X mutant, in which the mutation is part of the highly conserved and important CWxP motif in I MC4R i and other GPCRs [[37]], in transmembrane helix (TMH) 6, and the Q307X mutant with a PTC in the beginning of helix 8 showed a cell surface expression that was similar to the WT. Thus, in this study, we evaluated the hypothesis of a readthrough of stop mutations in combination with the synthetic I MC4R i ligand setmelanotide (SM) being a treatment option for obese patients carrying I MC4R i stop mutations and performed our investigation in a human cell model for the first time. Thus, we here evaluated whether treatment with the aminoglycoside G418 can rescue I MC4R i stop mutations and increase receptor expression as well as signaling in human MC4R-transfected HEK-293 cells. We conducted research on human HEK-293 cells transiently transfected with different I MC4R i stop mutations, as so far, a rescue of I MC4R i stop mutations has only been investigated in nonhuman COS-7 cells, focusing on G SB s sb signaling only, and the results were auspicious [[30]]. [Extracted from the article]

Obesity is a complex, multifactorial, lifestyle-related disorder which affects nearly one-third of the global population. In more than one way, obesity classifies as a potential indicator or contributing factor of various clinical conditions, subsequently leading to poor health outcomes and compromised quality of life (QoL). The high prevalence and reporting rate of obesity is irrespective of geographical difference, ethnicity and gender, however, they most often serve as predisposing risk factors for obesity. Additionally, environmental changes, availability & affordability of low nutrition, yet palatable food, hormonal disbalance and variation at the genetic level, prominently exacerbates the condition of obesity and its related effects. Clinically, obesity, may either lead to other pathophysiological conditions as well, such as liver dysfunction, polycystic ovarian syndrome, hypertension, coronary artery diseases and psychological impairment or vice-versa. Henceforth, to cope with the challenges of obesity and related conditions, a healthy lifestyle, personal care & social well-being is of prime importance. Additionally, a customized strategy to address the economic expenditure and newer therapeutic perspectives should be implemented to control the widespread damage of human population by this condition. The present review focuses on providing a brief knowledge about nutritional, biochemical, genetic and psychological aspects of obesity and its epidemiology. [ABSTRACT FROM AUTHOR]

Background Maternal prepregnancy obesity is an important risk factor for offspring obesity, which may partially operate through prenatal programming mechanisms. Objectives The study aimed to systematically identify prenatal metabolomic profiles mediating the intergenerational transmission of obesity. Methods We included 450 African-American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) Study pregnancy cohort. LC-MS was used to conduct metabolomic profiling on maternal plasma samples of the second trimester. The childhood growth outcomes of interest included BMI trajectories from birth to age 4 y (rising-high-, moderate-, and low-BMI trajectories) as well as overweight/obesity (OWO) risk at age 4 y. Mediation analysis was conducted to identify metabolite mediators linking maternal OWO and childhood growth outcomes. The potential causal effects of maternal OWO on metabolite mediators were examined using the Mendelian randomization (MR) method. Results Among the 880 metabolites detected in the maternal plasma during pregnancy, 14 and 11 metabolites significantly mediated the effects of maternal prepregnancy OWO on childhood BMI trajectories and the OWO risk at age 4 y, respectively, and 5 mediated both outcomes. The MR analysis suggested 6 of the 20 prenatal metabolite mediators might be causally influenced by maternal prepregnancy OWO, most of which are from the pathways related to the metabolism of amino acids (hydroxyasparagine, glutamate, and homocitrulline), sterols (campesterol), and nucleotides (N2,N2-dimethylguanosine). Conclusions Our study provides further evidence that prenatal metabolomic profiles might mediate the effect of maternal OWO on early childhood growth trajectories and OWO risk in offspring. The metabolic pathways, including identified metabolite mediators, might provide novel intervention targets for preventing the intrauterine development of obesity in the offspring of mothers with obesity. [ABSTRACT FROM AUTHOR]

Intervertebral disc degeneration (IVDD), for which obesity and genetics are known risk factors, is a chronic process that alters the structure and function of the intervertebral discs (IVD). Circulating leptin is positively correlated with body weight and is often measured to elucidate the pathogenesis of IVD degeneration. In this study, we examined the associations of LEP single nucleotide polymorphisms (SNPs) genetic and environmental effects with IVDD. A total of 303 Taiwanese patients with IVDD (mean age, 58.6 ± 12.7 years) undergoing cervical discectomy for neck pain or lumbar discectomy for back pain were enrolled. Commercially available enzyme-linked immunosorbent assay (ELISA) kits measured the circulating plasma leptin levels. TaqMan SNP genotyping assays genotyped the LEP SNPs rs2167270 and rs7799039. Leptin levels were significantly increased in obese individuals (p < 0.001) and non-obese or obese women (p < 0.001). In the dominant model, recoded minor alleles of rs2167270 and rs7799039 were associated with higher leptin levels in all individuals (p = 0.011, p = 0.012). Further, the association between these LEP SNPs and leptin levels was significant only in obese women (p = 0.025 and p = 0.008, respectively). There was an interaction effect between sex and obesity, particularly among obese women (interaction p = 0.04 and 0.02, respectively). Our findings demonstrate that these SNPs have sex-specific associations with BMI in IVDD patients, and that obesity and sex, particularly among obese women, may modify the LEP transcription effect. [ABSTRACT FROM AUTHOR]

Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader–Willi, fragile X, Bardet–Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (LEP), the leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1), the melanocortin 4 receptor (MC4R), single-minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), and the neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings. [ABSTRACT FROM AUTHOR]

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Background: Recent studies have shown that obesity is largely influenced by heredity and created by the interactions between several genes and environmental and behavioral factors. This study aimed to examine association between variant rs17782313 near melanocortin-4 receptor (MC4R) gene and behavioral and hormonal factors then evaluated interactions between variant MC4R rs17782313 with behavioral and hormonal factors on obesity. Methods: This cross-sectional study included 403 subjects, overweight and/or obesity, aged 20–50 years from Iran. The MC4R rs17782313 data were measured by the PCR–RFLP method. Dietary intake, physical activity, stress, anxiety, depression, appetite and emotional eating were assessed by using validated questionnaires. Ghrelin, glucagon-like peptide-1 and cortisol were measured by radioimmunoassay in plasma samples. Participants were also divided into three groups based on rs17782313 genotype and BMI. Results: After adjustment for age, gender, energy intake and PA, significant associations were observed between food intake, appetite, emotional eating, stress and physical activity with MC4R rs17782313 (p ˂0.05). Also, significant interactions were observed between fat intake (p-interaction = 0.002), protein intake (p-interaction = 0.01), energy intake (p-interaction = 0.01), emotional eating (p-interaction = 0.02), appetite (p-interaction = 0.04), stress (p-interaction = 0.04), ghrelin (p-interaction = 0.03), cortisol (p-interaction = 0.04) and physical activity (p-interaction = 0.04) and MC4R rs17782313 in terms of BMI. Conclusion: Interactions between the CC genotype and high intakes of fat and energy, emotional eating, high appetite, and too much stress with high levels of cortisol and ghrelin probably can have an effect on BMI in overweight/obese subjects. [ABSTRACT FROM AUTHOR]

Purpose: High-fat and low-fibre discretionary food intake and FTO genotype are each associated independently with higher risk of obesity. However, few studies have investigated links between obesity and dietary patterns based on discretionary food intake, and the interaction effect of FTO genotype are unknown. Thus, this study aimed to derive dietary patterns based on intake of discretionary foods, saturated fatty acids (SFA) and fibre, and examine cross-sectional associations with BMI and waist circumference (WC), and interaction effects of FTO genotype. Methods: Baseline data on 1280 adults from seven European countries were included (the Food4Me study). Dietary intake was estimated from a Food Frequency Questionnaire. Reduced rank regression was used to derive three dietary patterns using response variables of discretionary foods, SFA and fibre density. DNA was extracted from buccal swabs. Anthropometrics were self-measured. Linear regression analyses were used to examine associations between dietary patterns and BMI and WC, with an interaction for FTO genotype. Results: Dietary pattern 1 (positively correlated with discretionary foods and SFA, and inversely correlated with fibre) was associated with higher BMI (β:0.64; 95% CI 0.44, 0.84) and WC (β:1.58; 95% CI 1.08, 2.07). There was limited evidence dietary pattern 2 (positively correlated with discretionary foods and SFA) and dietary pattern 3 (positively correlated with SFA and fibre) were associated with anthropometrics. FTO risk genotype was associated with higher BMI and WC, with no evidence of a dietary interaction. Conclusions: Consuming a dietary pattern low in discretionary foods and high-SFA and low-fibre foods is likely to be important for maintaining a healthy weight, regardless of FTO predisposition to obesity. Trial registration: Clinicaltrials.gov NCT01530139. Registered 9 February 2012 https://clinicaltrials.gov/ct2/show/NCT01530139 [ABSTRACT FROM AUTHOR]

We examined the hypothesis that the genetic variants associated with abdominal obesity (AO) risk, excluding skeletal muscle mass impact, interact with lifestyle characteristics of adults aged >40 years in three cohorts from the Korean Genome and Epidemiology Study. Participants from a large city hospital‐based cohort, excluding those with cancers, thyroid diseases, chronic kidney disease or brain‐related diseases, were divided into AO (case; n = 17 545) and control (n = 36 283) using the cut‐offs for waist circumference of 90 cm for men and 85 cm for women. The genetic variants affecting AO risk were chosen from a genome‐wide association study in this cohort with obesity‐related covariates, including and excluding skeletal muscle mass as a covariate. The genetic variants were confirmed in the other two cohorts. The interaction between the genetic variants was identified by generalised multifactor dimensionality reduction analysis (GMDR). The polygenic risk scores (PRS)‐nutrient interactions were determined. Abdominal obesity was associated with SEC16B_rs543874, KCNQ5_rs2796052, CDKAL1_rs9356744, BDNF_rs6265, FTO_rs1421085, MC4R_rs17782313 and GIPR_rs1444988703 adjusting for covariates excluding LBM. However, the best model with 5 single nucleotide polymorphisms (SNP) contained COL3A1_rs3106801, ADAMTS3_rs13105983, KCNQ5_rs2796044, ZFHX3_rs9938769 and MIR17HG_rs7318578 from GMDR when including LBM in covariates. These genetic variants were specific for AO risk. The expression quantitative trait locus (eQTL) analysis showed that the SNP effects were associated with the corresponding gene expression. The high PRS with the 5 SNP model was positively associated with an increased risk of AO of 1.639 (1.463–1.836). The PRS interacted with the age of menarche, energy intake and physical activity. In conclusion, adults with a high PRS, particularly those experiencing early menarche, may particularly benefit from not exceeding energy requirements and from regular physical exercise in order to prevent abdominal obesity. This finding can be applied to personalised nutrition advice to prevent abdominal obesity. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) is the leading cause of death in women globally. Recent studies have reported that the minor allele (C allele) for melanocortin 4 receptor (MC4R) rs17782313 may be related to the incidence of obesity and the risk of CVD. Therefore, the present study aimed to investigate the interactions between the modified Nordic-style diet score (MND) and MC4R gene variant on markers of CVD. Methods: The current cross-sectional study was conducted on 282 Iranian women, aged 18–48 years, with a body mass index (BMI) ≥ 25. MND score was assessed using a 147 items food frequency questionnaire (FFQ). Genotyping of the MC4R (rs17782313) was conducted by the PCR method. The anthropometric measurements and serum profiles were assessed by standard protocols. Results: The means and standard deviation (SD) of age, weight, and BMI of individuals were 36.67 ± 9.10 years, 81.29 ± 12.43 kg, and 31.26 ± 4.29 kg/m2, respectively. The overall prevalence of rs17782313 genotypes was 30.1%, 24.8%, and 45.1% for TT, TC, and CC, respectively. Our results showed significant negative interactions between high MND score and rs17782313 SNP in terms of visceral fat level (VFL) (β: -10.84, 95% CI: -20.64 to -1.04, P = 0.03) and total cholesterol (β: -24.24, 95% CI: -49.87 to 1.38, P = 0.06) in the crude model. After adjusting confounders, the interaction between high MND scores and VFL remained significant. Conclusion: In conclusion, the results of the present study suggest that diet, gene variants, and their interaction should be considered in metabolic disease risk assessment. Further studies are needed to confirm these data and better elucidate the interaction. [ABSTRACT FROM AUTHOR]

Obesity is a chronic disease characterized by the abnormal or excessive accumulation of body fat, affecting more than 1 billion people worldwide. Obesity is commonly associated with other metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular diseases, chronic kidney disease, and cancers. Factors such as a sedentary lifestyle, overnutrition, socioeconomic status, and other environmental and genetic conditions can cause obesity. Many molecules and signaling pathways are involved in the pathogenesis of obesity, such as nuclear factor (NF)-κB, Toll-like receptors (TLRs), adhesion molecules, G protein-coupled receptors (GPCRs), programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and sirtuin 1 (SIRT1). Commonly used strategies of obesity management and treatment include exercise and dietary change or restriction for the early stage of obesity, bariatric surgery for server obesity, and Food and Drug Administration (FDA)-approved medicines such as semaglutide and liraglutide that can be used as monotherapy or as a synergistic treatment. In addition, psychological management, especially for patients with obesity and distress, is a good option. Gut microbiota plays an important role in obesity and its comorbidities, and gut microbial reprogramming by fecal microbiota transplantation (FMT), probiotics, prebiotics, or synbiotics shows promising potential in obesity and metabolic syndrome. Many clinical trials are ongoing to evaluate the therapeutic effects of different treatments. Currently, prevention and early treatment of obesity are the best options to prevent its progression to many comorbidities. [ABSTRACT FROM AUTHOR]

Background: Meta‐analyses suggest an association between autism spectrum disorder (ASD) and obesity, but the factors underlying this association remain unclear. This study investigated the association between ASD and obesity stratified on intellectual disability (ID). In addition, in order to gain insight into possible shared etiological factors, the potential role of shared familial liability was examined. Method: We studied a cohort of 3,141,696 individuals by linking several Swedish nationwide registers. We identified 35,461 individuals with ASD and 61,784 individuals with obesity. Logistic regression models were used to estimate the association between ASD and obesity separately by ID and sex and by adjusting for parental education, psychiatric comorbidity, and psychotropic medication. Potential shared familial etiologic factors were examined by comparing the risk of obesity in full siblings, maternal and paternal half‐siblings, and full‐ and half‐cousins of individuals with ASD to the risk of obesity in relatives of individuals without ASD. Results: Individuals with ASD + ID (OR = 3.76 [95% CI, 3.38–4.19]) and ASD−ID (OR = 3.40 [95% CI, 3.23–3.58]) had an increased risk for obesity compared with individuals without ASD. The associations remained statistically significant when adjusting for parental education, psychiatric comorbidity, and medication. Sex‐stratified analyses indicated a higher relative risk for males compared with females, with statistically significant interaction effects for ASD−ID, but not for ASD+ID in the fully adjusted model. First‐degree relatives of individuals with ASD+ID and ASD−ID had an increased risk of obesity compared with first‐degree relatives of individuals without ASD. The obesity risk was similar in second‐degree relatives of individuals with ASD+ID but was lower for and ASD−ID. Full cousins of individuals with ASD+ID had a higher risk compared with half‐cousins of individuals with ASD+ID). A similar difference in the obesity risk between full cousins and half‐cousins was observed for ASD−ID. Conclusions: Individuals with ASD and their relatives are at increased risk for obesity. The risk might be somewhat higher for males than females. This warrants further studies examining potential common pleiotropic genetic factors and shared family‐wide environmental factors for ASD and obesity. Such research might aid in identifying specific risks and underlying mechanisms in common between ASD and obesity. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes is a multifactorial disorder characterized by increased levels of free radicals. Both oxidative stress and obesity contribute to an inflammatory state of the disease, mainly by increasing the levels of the proinflammatory cytokine tumor necrosis factor-a (TNF-a). Considering that personal genetics may contribute to oxidative stress, this study assessed the impact of CAT C-262T polymorphism and GSTM1 and GSTT1 null polymorphisms on TNF-a levels in patients with type 2 diabetes. The study also evaluated whether the genetic variants act synergistically with obesity to increase TNF-a levels in patients with diabetes from Grande Vitória, Brazil. Methods: Fifty-six patients were included, of whom 28 were obese and 28 were nonobese. The CAT gene polymorphism was assessed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, whereas GSTM1 and GSTT1 polymorphisms were assessed using multiplex PCR. TNF-a levels were measured using the sandwich ELISA technique. Results: Frequencies of GSTM1 and GSTT1 null polymorphisms were 44.6% and 17.9%, respectively. The genotype frequencies of CAT C-262T polymorphism were 73.2%, 25.0%, and 1.8% for normal homozygote, heterozygote, and polymorphic homozygote, respectively. Polymorphic genotypes were not associated with increased TNF-a levels, and there was no significant increase in TNF-a levels when evaluating the synergism between obesity and personal genetics. Conclusion: The presence of CAT, GSTM1, and GSTT1 gene polymorphisms was not associated with increased TNF-a levels in patients with type 2 diabetes. Obesity alone or combined with personal genetics of CAT, GSTM1, and GSTT1 gene polymorphisms did not promote increased TNF-a levels in the study population. [ABSTRACT FROM AUTHOR]

Subcutaneous setmelanotide (IMCIVREE®), a melanocortin-4 receptor agonist, meets a previously unmet need and thus represents an important advancement in the management of patients with pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency obesity. Setmelanotide is the first approved treatment in patients aged ≥ 6 years with these conditions. In two single-arm, open-label, multicentre, phase III trials, subcutaneous setmelanotide was effective in reducing body weight by at least 10% from baseline after approximately 1 year of treatment at individualised therapeutic doses in patients aged ≥ 6 years with POMC, PCSK1 or LEPR deficiency obesity. Other outcomes relating to weight loss and self-reported hunger scores were also improved with setmelanotide therapy. Setmelanotide was generally well tolerated in clinical trials. Plain Language Summary: The causes of obesity are multifactorial, one of which is genetic mutations leading to deficiencies in key ligands and receptors involved in the leptin-melanocortin pathway in the brain that regulates hunger and body weight. While lifestyle interventions and bariatric surgery are available, there is a lack of pharmacological treatment options for obesity arising from genetic factors. Subcutaneous setmelanotide (IMCIVREE®) is the first treatment to be approved in the EU and the USA for patients aged ≥ 6 years with obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency. It works by activating the melanocortin-4 receptor, a crucial protein receptor in the leptin-melanocortin pathway, facilitating weight loss through hunger reduction and increased energy expenditure. In phase III trials, approximately one year of treatment with subcutaneous setmelanotide was associated with at least 10% weight reduction in a significant number of patients with POMC, PCSK1 or LEPR deficiency obesity. Improvements in other outcomes related to weight loss and self-reported hunger scores were also evident. Setmelanotide was generally well tolerated. Setmelanotide represents an important advancement in the management of patients with POMC, PCSK1 or LEPR deficiency obesity. [ABSTRACT FROM AUTHOR]

Aim: The underlying mechanisms connecting obesity and periodontal diseases remain unclear. This study investigates the potential causal association of obesity with periodontal diseases using Mendelian randomization (MR). Materials and Methods: Single‐nucleotide polymorphisms of obesity traits including body mass index (BMI), waist circumference (WC), and WC adjusted for BMI (WCadjBMI) from large‐scale genome‐wide association studies were screened for instrumental variables. The single trait periodontitis and the combined trait comprising periodontitis and loose teeth were adopted as surrogates for periodontal diseases. Inverse‐variance weighted (IVW), series of sensitivity analyses and multivariable MR were employed to determine the association of obesity with periodontal diseases. Results: IVW results showed that per 1‐SD increment in BMI (odds ratio, OR = 1.115; 95% confidence interval [CI] = 1.064–1.169; p <.001) and WC (OR = 1.117; 95% CI = 1.052–1.185; p <.001), but not WCadjBMI, were significantly associated with an increased risk of periodontitis/loose teeth. Moreover, the MR estimates were consistent across other MR sensitivity analyses and multivariable MR. However, a causal association of obesity with the single trait periodontitis was not identified. Conclusions: The presented evidence supports previous epidemiological findings by showing a potential causal association of genetic liability to obesity with periodontal diseases. The biological mechanisms underlying this association warrant further investigation. [ABSTRACT FROM AUTHOR]

Background: Both body mass index (BMI) and genetic factors independently contribute to cardiovascular disease (CVD). However, it is unclear whether genetic risk modifies the association between BMI and the risk of incident CVD. This study aimed to investigate whether BMI categories and genetic risk jointly and interactively contribute to incident CVD events, including hypertension (HTN), atrial fibrillation (AF), coronary heart disease (CHD), stroke, and heart failure (HF)., Methods: A total of 496,851 participants from the UK Biobank with one or more new-onset CVD events were included in the analyses. BMI was categorized as normal weight (< 25.0 kg/m 2 ), overweight (25.0-29.9 kg/m 2 ), and obesity (≥ 30.0 kg/m 2 ). Genetic risk for each outcome was defined as low (lowest tertile), intermediate (second tertile), and high (highest tertile) using polygenic risk score. The joint associations of BMI categories and genetic risk with incident CVD were investigated using Cox proportional hazard models. Additionally, additive interactions were evaluated., Results: Among the 496,851 participants, 270,726 (54.5%) were female, with a mean (SD) age was 56.5 (8.1) years. Over a median follow-up (IQR) of 12.4 (11.5-13.1) years, 102,131 (22.9%) participants developed HTN, 26,301 (5.4%) developed AF, 32,222 (6.9%) developed CHD, 10,684 (2.2%) developed stroke, and 13,304 (2.7%) developed HF. Compared with the normal weight with low genetic risk, the obesity with high genetic risk had the highest risk of CVD: HTN (HR: 3.96; 95%CI: 3.84-4.09), AF (HR: 3.60; 95%CI: 3.38-3.83), CHD (HR: 2.76; 95%CI: 2.61-2.91), stroke (HR: 1.44; 95%CI: 1.31-1.57), and HF (HR: 2.47; 95%CI: 2.27-2.69). There were significant additive interactions between BMI categories and genetic risk for HTN, AF, and CHD, with relative excess risk of 0.53 (95%CI: 0.43-0.62), 0.67 (95%CI: 0.51-0.83), and 0.37 (95%CI: 0.25-0.49), respectively., Conclusions: BMI and genetic factors jointly and interactively contribute to incident CVD, especially among participants with high genetic risk. These findings have public health implications for identifying populations more likely to have cardiovascular benefit from weight loss interventions., (© 2024. The Author(s).)

Fibroblast growth factor (FGF) 21, a hormone produced by the liver, improves glucose and lipid metabolism. We recently demonstrated that the FGF21 gene (Fgf21) underwent DNA demethylation in the mouse liver via peroxisome proliferator-activated receptor (PPAR) α during the fetal to lactation periods. Furthermore, we found that the DNA methylation state of Fgf21 was involved in obesity in adult animals. In the present study, we analyzed the DNA methylation state of the FGF21 gene (FGF21) in obese patients using genomic DNA extracted from human monocytes and macrophages and investigated the pathophysiological significance of the FGF21 expression response to pemafibrate (PM), a PPARα ligand. We examined 67 patients with obesity stratified into in- and outpatient cohorts. A positive correlation was observed between serum FGF21 levels and triglyceride (TG) levels before PM administration. However, changes in serum FGF21 levels following PM administration did not correlate with the FGF21 DNA methylation rate, except at one CpG site. The body mass index (BMI) and serum TG levels positively correlated with the FGF21 DNA methylation rate, particularly at different CpG positions. A negative correlation was observed between absolute changes in serum FGF21 levels and the ratio of change in serum TG levels after PM administration. Collectively, these results indicate the potential of FGF21 DNA methylation as a surrogate indicator of BMI and serum TG levels, while absolute changes in serum FGF21 levels after PM administration may offer prognostic insights into the efficacy of reducing serum TG levels through PM administration.

Objective: Rare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole-exome sequence data from 6803 longitudinally studied individuals., Methods: Exome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI z score > 2 (N = 279) but not observed in a child with a maximum BMI z score ≤ 0 (n = 1542) or that occurred in adults in the top 5th percentile of BMI (n = 263) but not in adults below the median BMI (n = 2629). Variants were then functionally analyzed using luciferase assays., Results: The comparisons between cases of obesity and controls identified eight missense variants in six genes: DYRK1B, KSR2, MC4R, NTRK2, PCSK1, and SIM1. Among these, MC4R p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that KSR2 p.I402F and p.T193I and NTRK2 p.S249Y alter protein function., Conclusions: In addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)