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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]

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]

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]

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]

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: 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]

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]

Fibroblast growth factor receptor 1 (FGFR1) is a widely expressed, membrane-bound receptor that transduces extracellular signals from FGF ligands and cadherins, resulting in intracellular signals influencing cellular growth, proliferation, calcium, and transcription. FGF21 and FGF2 stimulate the proliferation of tanycytes, specialized radial astrocytes along the ventricle of the hypothalamus, and influence metabolism. Tanycytes are in a privileged position between the cerebrospinal fluid, the blood supply in the median eminence, and neurons within nuclei in the hypothalamus. The effect of FGFR1 signaling upon tanycyte morphology and metabolism was examined in adult mice with conditional deletion of the Fgfr1 gene using the Fgfr1 flox/flox ; Nestin-Cre+ line. Loss of Fgfr1 resulted in shorter β tanycytes along the medial eminence. Control Fgfr1 flox/flox littermates and Fgfr1 flox/flox , Nestin-Cre+ (Fgfr1 cKO) knockout mice were placed on a 1-month long high-fat diet (HFD) or a normal-fat diet (NFD), to investigate differences in body homeostasis and tanycyte morphology under an obesity inducing diet. We found that FGFR1 is a vital contributor to tanycyte morphology and quantity and that it promotes stem cell maintenance in the hypothalamus and hippocampal dentate gyrus. The Fgfr1 cKO mice developed impaired tolerance to a glucose challenge test on a HFD without gaining more weight than control mice. The combination of HFD and loss of Fgfr1 gene resulted in altered β and α tanycyte morphology, and reduced stem cell numbers along the third ventricle of the hypothalamus and hippocampus., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Aim: The relationship between the gut microbiota, metabolites and body fat percentage (BFP) remains unexplored. We systematically assessed the causal relationships between gut microbiota, metabolites and BFP using Mendelian randomization analysis., Materials and Methods: Single nucleotide polymorphisms associated with gut microbiota, blood metabolites and BFP were screened via a genome-wide association study enrolling individuals of European descent. Summary data from genome-wide association studies were extracted from the MiBioGen consortium and the UK Biobank. The inverse variance-weighted model was the primary method used to estimate these causal relationships. Sensitivity analyses were performed using pleiotropy, Mendelian randomization-Egger regression, heterogeneity tests and leave-one-out tests., Results: In the aspect of phyla, classes, orders, families and genera, we observed that o&#95;Bifidobacteriales [β = -0.05; 95% confidence interval (CI): -0.07 to -0.03; false discovery rate (FDR) = 2.76 × 10 -3 ], f&#95;Bifidobacteriaceae (β = -0.05; 95% CI: -0.07 to -0.07; FDR = 2.76 × 10 -3 ), p&#95;Actinobacteria (β = -0.06; 95% CI: -0.09 to -0.03; FDR = 6.36 × 10 -3 ), c&#95;Actinobacteria (β = -0.05; 95% CI: -0.08 to -0.02; FDR = 1.06 × 10 -2 ), g&#95;Bifidobacterium (β = -0.05; 95% CI: -0.07 to -0.02; FDR = 1.85 × 10 -2 ), g&#95;Ruminiclostridium9 (β = -0.03; 95% CI: -0.06 to -0.01; FDR = 4.81 × 10 -2 ) were negatively associated with BFP. G&#95;Olsenella (β = 0.02; 95% CI: 0.01-0.03; FDR = 2.16 × 10 -2 ) was positively associated with BFP. Among the gut microbiotas, f&#95;Bifidobacteriales, o&#95;Bifidobacteriales, c&#95;Actinobacteria and p&#95;Actinobacteria were shown to be significantly associated with BFP in the validated dataset. In the aspect of metabolites, we only observed that valine (β = 0.77; 95% CI: 0.5-1.04; FDR = 8.65 × 10 -6 ) was associated with BFP., Conclusions: Multiple gut microbiota and metabolites were strongly associated with an increased BFP. Further studies are required to elucidate the mechanisms underlying this putative causality. In addition, BFP, a key indicator of obesity, suggests that obesity-related interventions can be developed from gut microbiota and metabolite perspectives., (© 2024 John Wiley & Sons Ltd.)

Aim: To test the hypothesis that liver-expressed antimicrobial peptide 2 (LEAP2) genetic variants might influence the susceptibility to human obesity., Methods: Using data from the UK Biobank, we identified independent LEAP2 gene single nucleotide polymorphisms (SNPs) and examined their associations with obesity traits and serum insulin-like growth factor-1 (IGF-1) concentration. These associations were evaluated for both individual SNPs and after combining them into a genetic risk score (GRS LEAP2 ) using linear and logistic regression models. Sex-stratified analyses were also conducted., Results: Five SNPs showed positive associations with obesity-related traits. rs57880964 was associated with body mass index (BMI) and waist-to-hip ratio adjusted for BMI (WHRadjBMI), in the total population and among women. Four independent SNPs were positively associated with higher serum IGF-1 concentrations in both men and women. GRS LEAP2 was associated with BMI and WHRadjBMI only in women and with serum IGF-1 concentration in both sexes., Conclusions: These findings reveal sex-specific associations between key LEAP2 gene variants and several obesity traits, while also indicating a strong independent association of LEAP2 variants with serum IGF-1 concentration., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: To explore the potential association between the KLF14 rs4731702 polymorphism and metabolic syndrome traits among patients diagnosed with type 1 diabetes (T1D)., Methods: The study group included 350 patients with T1D and 250 healthy control subjects. The analysis focused on the genotyping of KLF14 rs4731702 single nucleotide polymorphism (SNP), as well as evaluating serum concentrations of inflammatory markers, blood pressure, lipid profiles, and the quantitative status of CD4 + CD25highFOXP3+ T cells., Results: Patients with T1D carrying the T allele of KLF14 rs4731702 SNP had higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, as well as lower glycated haemoglobin and serum concentration of proinflammatory markers than C allele carriers. They also developed hypertension less often than carriers of the C allele. The analysis of CD4 + CD25highFOXP3+ regulatory T-cell status based on KLF14 genotype showed that, in T1D patients, those with the TT genotype had the highest frequency of these cells compared to carriers of the CC and CT genotypes., Conclusion: Our study suggests that the T allele of the KLF14 rs4731702 SNP might confer a protective effect against the development of obesity, hypertension, dyslipidaemia, and chronic inflammatory state in patients diagnosed with T1D., (© 2024 John Wiley & Sons Ltd.)

Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader-Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication., (© 2024 The Authors. Clinical Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Objectives: The proprotein convertase subtilisin/Kexin type 1 gene (PCSK1) is implicated in hypothalamic appetite control. Several studies have addressed the relationship between PCSK1 polymorphisms and obesity, although conflicting results were observed. We tested the potential association of four PCSK1 variants with the risk of overweight/obesity and related variables in Portuguese children., Methods: This is a case-control study, where four PCSK1 variants, rs6230 (c.-101T>C), rs6232 (p.N221D), rs6235 (p.S690T), and rs3811942 (c.*265T>C), were analyzed in Portuguese children (aged 5-13 years-old). Anthropometric measures were objectively collected and used to provide weight-for-age, height-for-age, and body mass index (BMI) for age. The indices generated were compared to standard reference values of WHO to obtain the corresponding Z-scores., Results: Logistic regression, in the dominant model, revealed no significant associations between the four individual PCSK1 variants and the risk of overweight/obesity in the total population. However, stratifying the sample by sex, a marginally significant association was found between the rs6235 minor C-allele and increased overweight/obesity in boys (n = 345) (OR 1.55 [1.01-2.38] p = .044), but not in girls (n = 340) (OR 0.73 [0.46-1.14] p = .169). Consistently, boys with genotype GG presented lower BMI Z-score (0.62) when compared to those with the genotypes GC + CC (1.04). Testing for different effects in males versus females, a significant interaction was found between the rs6235 polymorphism and sex for BMI Z-score (p = .025)., Conclusions: Results of this study suggest for a sex-differentiated association between PCSK1 rs6235 and overweight/ obesity in Portuguese children., (© 2023 Wiley Periodicals LLC.)

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future., (© 2024 John Wiley & Sons Ltd.)

Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by early-onset obesity, polydactyly, genital and kidney anomalies, developmental delay and vision loss due to rod-cone dystrophy. BBS is an autosomal recessive disorder with >20 implicated genes. The genotype-phenotype relationship in BBS is not clear, and there may be additional modifying factors. The underlying mechanism is dysfunction of primary cilia. In BBS, receptor trafficking in and out of the cilia is compromised, affecting multiple organ systems. Along with early-onset obesity, hyperphagia is a prominent symptom and contributes significantly to clinical morbidity and caregiver burden. While there is no cure for BBS, setmelanotide is a new pharmacotherapy approved for treatment of obesity in BBS. The differential diagnosis for BBS includes other ciliopathies, such as Alstrom syndrome, and other genetic obesity syndromes, such as Prader-Willi syndrome. Careful clinical history and genetic testing can help determine the diagnosis and a multidisciplinary team is necessary to guide clinical management., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Over the past few decades, there has been a global surge in the prevalence of obesity, rendering it a globally recognized epidemic. Contrary to simply being a medical condition, obesity is an intricate disease with a multifactorial aetiology. Understanding the precise cause of obesity remains a challenge; nevertheless, there seems to be a complex interplay among biological, psychosocial and behavioural factors. Studies on the genetic factors of obesity have revealed several pathways in the brain that play a crucial role in food intake regulation. The best characterized pathway, thus far, is the leptin-melanocortin pathway, from which disruptions are responsible for the majority of monogenic obesity disorders. The effectiveness of conservative lifestyle interventions in addressing monogenic obesity has been limited. Therefore, it is crucial to complement the management strategy with pharmacological and surgical options. Emphasis has been placed on developing drugs aimed at replacing the absent signals, with the goal of restoring the pathway. In both monogenic and polygenic forms of obesity, outcomes differ across various interventions, likely due to the multifaceted nature of the disease. This underscores the need to explore alternative therapeutic strategies that can mitigate this heterogeneity. Precision medicine can be regarded as a powerful tool that can address this concern, as it values the understanding of the underlying abnormality triggering the disease and provides a tailored treatment accordingly. This would assist in optimizing outcomes of the current therapeutic approaches and even aid in the development of novel treatments capable of more effectively managing the global obesity epidemic., (© 2024 John Wiley & Sons Ltd.)

Aim: To assess the sex- and time-specific causal effects of obesity-related anthropometric traits on glycaemic traits., Materials and Methods: We used univariate and multivariate Mendelian randomization to assess the causal associations of anthropometric traits (gestational variables, birth weight, childhood body mass index [BMI], BMI, waist-to-hip ratio [WHR], BMI-adjusted WHR [WHR adj BMI]) with fasting glucose and insulin in Europeans from the Early Growth Genetics Consortium (n ≤ 298 142), the UK Biobank, the Genetic Investigation of Anthropometric Traits Consortium (n ≤ 697 734; females: n ≤ 434 794; males: n ≤ 374 754) and the Meta-Analyses of Glucose and Insulin-related traits Consortium (n ≤ 151 188; females: n ≤ 73 089; males: n ≤ 67 506), adjusting for maternal genetic effects, smoking, alcohol consumption, and age at menarche., Results: We observed a null association for gestational variables, a negative association for birth weight, and positive associations for childhood BMI and adult traits (BMI, WHR, and WHR adj BMI). In female participants, increased birth weight causally decreased fasting insulin (beta IVW , -0.07, 95% confidence interval [CI] -0.11 to -0.03; p = 1.92 × 10 -3 ), but not glucose levels, which was annulled by adjusting for age at menarche. In male participants, increased birth weight causally decreased fasting glucose (beta inverse-variance-weighted (IVW) , -0.07, 95% CI -0.11 to -0.03; p = 3.22 × 10 -4 ), but not insulin levels. In time-specific analyses, independent effects of birth weight were absent in female participants, and were more pronounced in male participants. Independent effects of childhood BMI were attenuated in both sexes; independent effects of adult traits differed by sex., Conclusions: Our findings provide evidence for causal and independent effects of sex- and time-specific anthropometric traits on glycaemic variables, and highlight the importance of considering multiple obesity exposures at different time points in the life course., (© 2024 John Wiley & Sons Ltd.)

There is a genetic component to human obesity that accounts for 40% to 50% of the variability in body weight status but that is lower among normal weight individuals (about 30%) and substantially higher in the subpopulation of individuals with obesity and severe obesity (about 60%-80%). The appreciation that heritability varies across classes of BMI represents an important advance. After controlling for BMI, ectopic fat and fat distribution traits are characterized by heritability levels ranging from 30% to 55%. Defects in at least 15 genes are the cause of monogenic obesity cases, resulting mostly from deficiencies in the leptin-melanocortin signaling pathway. Approximately two-thirds of the BMI heritability can be imputed to common DNA variants, whereas low-frequency and rare variants explain the remaining fraction. Diminishing allele effect size is observed as the number of obesity-associated variants expands, with most BMI-increasing or -decreasing alleles contributing only a few grams or less to body weight. Obesity-promoting alleles exert minimal effects in normal weight individuals but have larger effects in individuals with a proneness to obesity, suggesting a higher penetrance; however, it is not known whether these larger effect sizes precede obesity or are caused by an obese state. The obesity genetic risk is conditioned by thousands of DNA variants that make genetically based obesity prevention and treatment a major challenge. [ABSTRACT FROM AUTHOR]

Obesity is an important risk factor associated with non‐communicable cardiometabolic diseases. Previous studies have indicated that children and adolescents with a predisposed genetic risk for obesity could benefit from an active lifestyle, but there are no studies investigating whether physical fitness moderates the association of genetics and obesity. The aim of this study was to verify the moderating role of physical fitness in the relationship between genetic risk score (GRS) and body mass index (BMI) in children and adolescents. This cross‐sectional study was carried out with 1471 children and adolescents, aged between 6 and 17 years from Santa Cruz do Sul, Brazil. Weight and height were assessed to determine BMI. Physical fitness components (cardiorespiratory fitness [CRF], lower limb strength [LLS], upper limb strength, and abdominal strength) were evaluated. The GRS was based on previously associated obesity single‐nucleotide polymorphism rs9939609 (FTO), rs6548238 (TMEM18), and rs16835198 (FNDC5). Moderation analyses were tested using linear regression models, and the interactions were represented by physical fitness components X GRS (categorical variable). All analyses were adjusted for skin color/ethnicity, sex, and sexual maturation. Significant interactions for CRF (P = 0.041), LLS (P = 0.041), and abdominal strength (P = 0.046) X 5 and 6 risk alleles with BMI were found only in adolescents. In addition, there was evidence that fitness components attenuated the high genetic predisposition to high BMI. Physical fitness components are moderators in the relationship between GRS and BMI in adolescents. These findings highlight the need for interventions targeting to improve this aspect, which is an important health indicator in all ages. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between obesity‐related traits and risk of rheumatoid arthritis (RA). Methods: We conducted genetic correlation analysis and a 2‐sample Mendelian randomization (MR) study, using genome‐wide genetic data based on >850,000 individuals of European ancestry. Summary statistics were collected from the largest genome‐wide association study conducted to date for body mass index (BMI; n = 806,810), waist‐to‐hip ratio (WHR; n = 697,734), WHR adjusted for BMI (WHRadjBMI; n = 694,649), and RA (ncase = 14,361, ncontrol = 43,923). We conducted cross‐trait linkage disequilibrium score regression and ρ‐HESS analyses to quantify genetic correlation between pairs of traits (causal overlap). For each obesity‐related exposure, we utilized independent, genome‐wide significant single‐nucleotide polymorphisms (P < 5 × 10−9) as instruments to perform MR analysis (causal relationship). We interrogated the causal relationship both in the general population and in a sex‐specific manner and calculated odds ratios (ORs) and 95% confidence intervals (95% CIs). Sensitivity analyses were performed to validate MR model assumptions. Results: Despite a negligible overall genetic correlation between the 3 obesity‐related traits and RA, we found significant local genetic correlations at several regions on chromosome 6 (positions 28–29M, 30–35M, and 50–52M), highlighting a shared genetic basis. We further observed an increased risk of RA per SD increment (4.8 kg/m2) in genetically predicted BMI (OR 1.22 [95% CI 1.09–1.37]). The effect was consistent across sensitivity analyses and comparable between sexes (OR 1.22 [95% CI 1.04–1.44] in male subjects and 1.19 [95% CI 1.04–1.36] in female subjects). However, we did not find evidence supporting a causal role of either WHR (OR 0.98 [95% CI 0.84–1.14]) or WHRadjBMI (OR 0.90 [95% CI 0.79–1.04]) in RA. Conclusion: Genetically predicted BMI significantly increases RA risk. Future studies are needed to understand the biologic mechanisms underlying this link. [ABSTRACT FROM AUTHOR]

Aim: To examine the real-world efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in monogenic obesity in patients with Alström syndrome (ALMS)., Methods: We screened 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index of 25 kg/m 2 or higher, insulin resistance, suboptimal glycaemic control on antihyperglycaemic medications or non-alcoholic fatty liver disease., Results: In total, 30 patients, with a mean age of 31 ± 11 years and a male to-female ratio of 2:1, completed 6 months of treatment with GLP-1 RAs either in the form of semaglutide or exenatide. On average, treatment with GLP-1 RAs reduced body weight by 5.4 ± 1.7 (95% confidence interval [CI] 3.6-7) kg and HbA1c by 12 ± 3.3 (95% CI 8.7-15.3) mmol/mol, equating to 6% weight loss (P < .01) and 1.1% absolute reduction in HbA1c (P < .01). Significant improvements were also observed in serum total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic variables in our cohort of monogenic syndromic obesity was comparable with data for polygenic obesity, irrespective of weight loss., Conclusions: Data from our centre highlight the non-inferiority of GLP-1 RAs in monogenic syndromic obesity to the available GLP-1 RA-use data in polygenic obesity, therefore, these agents can be considered as a treatment option in patients with ALMS, as well as other forms of monogenic obesity., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Perinatal exposure to maternal obesity predisposes offspring to develop obesity later in life. Immune dysregulation in the hypothalamus, the brain center governing energy homeostasis, is pivotal in obesity development. This study aimed to identify key candidate genes associated with the risk of offspring obesity in maternal obesity., Methods: We obtained obesity-related datasets from the Gene Expression Omnibus (GEO) database. GSE135830 comprises gene expression data from the hypothalamus of mouse offspring in a maternal obesity model induced by a high-fat diet model (maternal high-fat diet (mHFD) group and maternal chow (mChow) group), while GSE127056 consists of hypothalamus microarray data from young adult mice with obesity (high-fat diet (HFD) and Chow groups). We identified differentially expressed genes (DEGs) and module genes using Limma and weighted gene co-expression network analysis (WGCNA), conducted functional enrichment analysis, and employed a machine learning algorithm (least absolute shrinkage and selection operator (LASSO) regression) to pinpoint candidate hub genes for diagnosing obesity-associated risk in offspring of maternal obesity. We constructed a nomogram receiver operating characteristic (ROC) curve to evaluate the diagnostic value. Additionally, we analyzed immune cell infiltration to investigate immune cell dysregulation in maternal obesity. Furthermore, we verified the expression of the candidate hub genes both in vivo and in vitro., Results: The GSE135830 dataset revealed 2868 DEGs between the mHFD offspring and the mChow group and 2627 WGCNA module genes related to maternal obesity. The overlap of DEGs and module genes in the offspring with maternal obesity in GSE135830 primarily enriched in neurodevelopment and immune regulation. In the GSE127056 dataset, 133 DEGs were identified in the hypothalamus of HFD-induced adult obese individuals. A total of 13 genes intersected between the GSE127056 adult obesity DEGs and the GSE135830 maternal obesity module genes that were primarily enriched in neurodevelopment and the immune response. Following machine learning, two candidate hub genes were chosen for nomogram construction. Diagnostic value evaluation by ROC analysis determined Sytl4 and Kncn2 as hub genes for maternal obesity in the offspring. A gene regulatory network with transcription factor-miRNA interactions was established. Dysregulated immune cells were observed in the hypothalamus of offspring with maternal obesity. Expression of Sytl4 and Kncn2 was validated in a mouse model of hypothalamic inflammation and a palmitic acid-stimulated microglial inflammation model., Conclusion: Two candidate hub genes (Sytl4 and Kcnc2) were identified and a nomogram was developed to predict obesity risk in offspring with maternal obesity. These findings offer potential diagnostic candidate genes for identifying obesity-associated risks in the offspring of obese mothers., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Pathogenic variants in pleckstrin homology domain interacting protein (PHIP) are associated with Chung-Jansen syndrome characterized by developmental delay, intellectual disability, behavioral challenges, hypotonia, obesity, and dysmorphic features. We report phenotypes and genotypes of 47 individuals with likely pathogenic/pathogenic PHIP variants. Variants were de novo in 61.7%, unknown inheritance in 29.8%, and inherited in 8.5%. The median age of the individuals was 10.9 years, approximately equally divided by sex. Individuals in this cohort frequently had a history of developmental delay (85.1%), attention-deficit/hyperactivity disorder (51.1%), anxiety (46.8%), depression (27.7%), and sleep difficulties (42.6%). Depression was significantly higher in the older age group (>12 years old). Most individuals had moderately low adaptive functioning based on the Vineland-3 (mean = 76.8, standard deviation = 12.0). Overall, 55.8% of individuals were obese/overweight. The percentage of obese individuals was greater in the older age group (>12 years old) and evolves over time. Other common symptoms were hypotonia (78.7%), constipation (48.9%), visual problems (66%), and cryptorchidism (39.1% of males). Our findings provide additional natural history data for Chung-Jansen syndrome and provide opportunities for early intervention of healthy eating habits and awareness of developing mood and behavioral challenges over the life course., (© 2023 Wiley Periodicals LLC.)

Background: The current knowledge about the molecular mechanisms underlying the health benefits of exercise is still limited, especially in childhood. We set out to investigate the effects of a 20-week exercise intervention on whole-blood transcriptome profile (RNA-seq) in children with overweight/obesity., Methods: Twenty-four children (10.21 ± 1.33 years, 46% girls) with overweight/obesity, were randomized to either a 20-week exercise program (intervention group; n = 10), or to a no-exercise control group (n = 14). Whole-blood transcriptome profile was analyzed using RNA-seq by STRT technique with GlobinLock technology., Results: Following the 20-week exercise intervention program, 161 genes were differentially expressed between the exercise and the control groups among boys, and 121 genes among girls (p-value <0.05), while after multiple correction, no significant difference between exercise and control groups persisted in gene expression profiles (FDR >0.05). Genes enriched in GO processes and molecular pathways showed different immune response in boys (antigen processing and presentation, infections, and T cell receptor complex) and in girls (Fc epsilon RI signaling pathway) (FDR <0.05)., Conclusion: These results suggest that 20-week exercise intervention program alters the molecular pathways involved in immune processes in children with overweight/obesity., (© 2023 The Authors. American Journal of Human Biology published by Wiley Periodicals LLC.)

Background: Obesity is accompanied by dysregulated inflammation, which can contribute to vasculometabolic complications including metabolic syndrome and atherosclerosis. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular diseases. We aimed to determine how CHIP is related to immune cell function, systemic inflammation, and vasculometabolic complications in obese individuals., Methods and Results: Two hundred ninety-seven individuals with overweight and obesity, between the ages of 54 and 81 years, were recruited in a cross-sectional study. Clonal hematopoiesis driver mutations (CHDMs) were identified with an ultrasensitive targeted assay. Assessment of carotid artery atherosclerosis was performed with ultrasound. Detailed immunological parameters, including cytokine production capacity of peripheral blood mononuclear cells, and targeted plasma proteomics analysis, were studied. Adipose tissue inflammation was determined in subcutaneous fat biopsies. Individuals with CHIP had higher concentrations of circulating IL (interleukin)-6. Total number of leukocytes and neutrophils were higher in individuals with CHIP. In contrast, ex vivo cytokine production capacity of peripheral blood mononuclear cells was significantly lower in individuals with CHIP. Sex-stratified analysis showed that men with CHDMs had significantly higher leukocyte and neutrophil counts, and ex vivo cytokine production capacity was lower in women with CHDMs. Surprisingly, the presence of atherosclerotic plaques was significantly lower in individuals with CHDMs. There was no relation between CHIP and metabolic syndrome., Conclusions: In individuals with overweight or obesity, CHDMs are not associated with vasculometabolic complications, but rather with a lower presence of carotid plaques. CHDMs associate with increased circulating inflammatory markers and leukocyte numbers, but a lower peripheral blood mononuclear cell cytokine production capacity.

Background: The causal relationship between obesity-related anthropometric indicators/body composition and erectile dysfunction has not been established in previous observational studies., Method: We screened single nucleotide polymorphisms significantly associated with exposure from genome-wide association studies as instrumental variables (p < 5.0 × 10 -8 ). The summary statistics for erectile dysfunction were collected from a genome-wide association study with a sample size of 223,805. Exposure and outcome populations included are of European ancestry. We used univariate and multivariate Mendelian randomization (i) to investigate the causal relationship between genetically predicted obesity-related anthropometric indicators/body composition and erectile dysfunction and (ii) to examine the mediating role of coronary artery disease. Mendelian randomization analysis was conducted using an inverse variance weighted method. A series of sensitivity analyses validated the results of the Mendelian randomization analysis. Causal estimates are expressed as odds ratios with 95% confidence intervals., Results: Obesity-related anthropometric indicators/body composition were associated with an increased risk of erectile dysfunction in univariate Mendelian randomization analyses. For the 1-SD increase in body mass index, the odds ratio was 1.841 (95% confidence interval: 1.049-1.355, p = 0.006). For the 1-SD increase in waist circumference and hip circumference, the odds ratios were 1.275 (95% confidence interval: 1.101-1.478, p = 0.001) and 1.156 (95% confidence interval: 1.015-1.317, p = 0.009), respectively. The odds ratio for the 1-SD increase in whole body fat mass was 1.221 (95% confidence interval: 1.047-1.388, p = 0.002). For the 1-SD increase in leg fat percentage (left and right), the odds ratios were 1.256 (95% confidence interval: 1.006-1.567, p = 0.044) and 1.285 (95% confidence interval: 1.027-1.608, p = 0.028), respectively. For the 1-SD increase in leg fat mass (left and right), the odds ratios were 1.308 (95% confidence interval: 1.108-1.544, p = 0.001) and 1.290 (95% confidence interval: 1.091-1.524, p = 0.003), respectively. For the 1-SD increase in arm fat mass (left and right), the odds ratios were 1.269 (95% confidence interval: 1.113-1.447, p < 0.001) and 1.254, respectively. Multivariate Mendelian randomization analysis showed that after adjusting for coronary artery disease, some genetic predispositions to obesity-related anthropometric indicators and body composition were still associated with an increased risk of erectile dysfunction. Significant associations were found for waist circumference-erectile dysfunction (odds ratio: 1.218, 95% confidence interval: 1.036-1.432), leg fat percentage (left)-erectile dysfunction (odds ratio: 1.245, 95% confidence interval: 1.035-1.497), leg fat mass (left)-erectile dysfunction (odds ratio: 1.264, 95% confidence interval: 1.051-1.521), arm fat mass (right)-erectile dysfunction (odds ratio: 1.186, 95% confidence interval: 1.024-1.373), and arm fat mass (left)-erectile dysfunction (odds ratio: 1.17, 95% confidence interval: 1.018-1.360). Meanwhile, coronary artery disease mediated the effects of fat on erectile dysfunction, and the proportion of coronary artery disease-mediated cases ranged from 10% to 22%., Conclusion: There is a potential causal relationship between obesity-related anthropometric indicators/body composition and erectile dysfunction. Higher waist circumference, leg fat percentage, and arm fat mass may increase the risk of erectile dysfunction, and coronary artery disease partly mediates this overall effect. Understanding the causal relationship between obesity and erectile dysfunction and the mediating role of coronary artery disease may provide more information for erectile dysfunction intervention and prevention strategies., (© 2023 American Society of Andrology and European Academy of Andrology.)

Background: The extent to which obesity and genetics determine postoperative complications is incompletely understood. Methods: We performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990 and 2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome-wide genotyping data to the Electronic Medical Records and Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease-9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score was constructed from 97 obesity-risk single-nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk of obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components. Results: Individuals with overweight or obese BMI (≥25 kg/m2) had increased risk of incisional hernia (odds ratio [OR] 1.7–5.5, p < 3.1 × 10−20), and people with obesity (BMI ≥ 30 kg/m2) had increased risk of postoperative infection (OR 1.2–2.3, p < 2.5 × 10−5). In the eMERGE cohort, genetically predicted BMI was associated with incisional hernia (OR 2.1 [95% CI 1.8–2.5], p = 1.4 × 10−6) and postoperative infection (OR 1.6 [95% CI 1.4–1.9], p = 3.1 × 10−6). Association findings were similar after limitation of the cohorts to those who underwent abdominal procedures. Conclusions: Clinical and Mendelian randomization studies suggest that obesity, as measured by BMI, is associated with the development of postoperative incisional hernia and infection. [ABSTRACT FROM AUTHOR]

Background and Aims: The heritability of nonalcoholic fatty liver disease (NAFLD) in lean individuals is undetermined. This familial aggregation study aimed to evaluate familial linkage for NAFLD and the risk of NAFLD among first-degree relatives of probands with lean NAFLD., Methods: This study prospectively recruited cohorts of probands with lean NAFLD, probands with obese NAFLD, and lean probands with non-NAFLD and their respective first-degree relatives. A total of 257 participants were evaluated for liver steatosis, defined by the controlled attenuation parameter ≥288 dB/m 2 , metabolic characteristics, and the PNPLA3, TM6SF2, and MBOAT7 polymorphisms., Results: The prevalence of NAFLD in first-degree relatives of lean NAFLD probands (39.9%) was similar to that in the obese NAFLD group (36.9%) and was significantly higher than in lean persons without NAFLD (19.1%). First-degree relatives of probands with NAFLD who were male, and had central obesity, hypertriglyceridaemia, insulin resistance, and the PNPLA3 rs738409C>G allele had a significantly higher prevalence of NAFLD. After multivariable adjustment for gender, metabolic characteristics, and the PNPLA3 rs738409C>G allele, first-degree relatives of probands with lean NAFLD (odds ratio [OR], 5.13; 95% CI, 1.77-14.86) and obese NAFLD (OR, 3.20; 95% CI, 1.14-8.99) exhibited an increased risk of NAFLD compared with those of lean controls without NAFLD., Conclusions: Our well-phenotype cohorts revealed familial clustering of NAFLD and higher risks of NAFLD in first-degree relatives of probands with lean or obese NAFLD. The findings encourage clinicians caring for NAFLD patients to be more vigilant for NAFLD in their family members., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Compromised adipose tissue plasticity is a hallmark finding of obesity orchestrated by the intricate interplay between various extracellular matrix components. Collagen6 (COL6) is well characterized in obese visceral adipose tissue (VAT), not much is known about MMP14 which is hypothesized to be the key player in matrix reorganization. Subjects with obesity (BMI ≥40; n = 50) aged 18-60 years undergoing bariatric surgery and their age-matched controls (BMI < 25; n = 30) were included. MMP14, Col6A3 and Tissue inhibitor of metalloproteinase 2 (TIMP2) mRNA expression was assessed in VAT and their serum levels along with endotrophin were estimated in both groups preoperatively and post-operatively in the obese group. The results were analysed statistically and correlated with anthropometric and glycaemic parameters, namely fasting glucose and insulin, HbA1c, HOMA-IR, HOMA-β and QUICKI. Circulating levels as well as mRNA expression profiling revealed significant differences between the individuals with and without obesity (p < .05), more so in individuals with diabetes and obesity (p < .05). Follow-up serum analysis revealed significantly raised MMP14 (p < .001), with decreased Col6A3, endotrophin and TIMP2 levels (p < .01, p < .001 and p < .01, respectively). A rise in serum MMP14 protein, simultaneous with post-surgical weight loss and decreased serum levels of associated extracellular matrix (ECM) remodellers, suggests its crucial role in modulating obesity-associated ECM fibrosis and pliability of VAT., (© 2023 World Obesity Federation.)

Obesity is an escalating global health problem affecting both humans and companion animals. In cats it is associated with increased mortality and multiple diseases, including diabetes mellitus. Two genes coding for proteins known to play a critical role in energy homeostasis across species are the proopiomelanocortin (POMC) gene and the melanocortin-4 receptor (MC4R) gene. A missense variant in the coding sequence of the feline MC4R (MC4R:c.92C>T) has been reported to be associated with diabetes and overweight in domestic shorthair cats, and while variants in the POMC gene are known to cause obesity in humans and dogs, variants in POMC and their association with feline obesity and diabetes mellitus have not been investigated to date. The current study aimed to assess the association between the previously described MC4R variant and body condition score (BCS), as well as body fat content (%BF) in 89 non-diabetic domestic shorthair cats. Furthermore, we investigated the feline POMC gene as a potential candidate gene for obesity. Our results indicate that the MC4R:c.92C>T polymorphism is not associated with BCS or %BF in non-diabetic domestic shorthair cats. The mutation analysis of all POMC exons identified two missense variants, with a variant in exon 1 (c.28G>C; p.G10R) predicted to be damaging. The variant was subsequently assessed in all 89 cats, and cats heterozygous for the variant had a significantly increased body condition score (p = 0.03) compared with cats homozygous for the wild-type allele. Results from our study provide additional evidence that the previously described variant in MC4R is not associated with obesity in domestic shorthair cats. More importantly, we have identified a novel variant in the POMC gene, which might play a role in increased body condition score and body fat content in domestic shorthair cats., (© 2023 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.)

Obesity is often accompanied with psychosocial adjustment problems, such as difficulties in social interactions and social withdrawal. A key aspect of social cognition is theory of mind, which allows inferring mental states, feelings, motivations, and beliefs of others and to use this information to predict their future behaviour. Theory of mind is highly dependent on prefrontal dopaminergic neurotransmission, which is regulated by catechol‐O‐methyltransferase (COMT) activity. We aimed at determining whether theory of mind is altered in obesity and if this ability is modulated by COMT. Fifty patients with obesity and 47 normal‐weight individuals underwent the Reading the Mind in the Eyes Test, the Wisconsin Card Sorting Test, and the Vocabulary subscale of the Wechsler Adult Intelligence Scale. The genotype for the COMT Val 158Met functional polymorphism was determined for all subjects. Patients with obesity obtained significantly lower scores in the negative items of the Reading the Mind in the Eyes Test than normal‐weight subjects. Further, an interaction effect was observed between group and COMT genotype. Specifically, the presence of the Met allele was associated to a better identification of negative mental states only in patients with obesity. Our results indicate that obesity is accompanied with difficulties in theory of mind and that this ability is influenced by the COMT genotype. [ABSTRACT FROM AUTHOR]

"Psychological essentialism" refers to our tendency to view the natural world as emerging from the result of deep, hidden, and internal forces called "essences." People tend to believe that genes underlie a person's identity. People encounter information about genetics on a regular basis, as through media such as a New York Times piece "Infidelity Lurks in Your Genes" or a 23andMe commercial showing people acquiring new ethnic identities as the result of their genotyping. How do people make sense of new scientific findings that are inherently complex if they don't have years of specialized training and education at their disposal? Given the substantial overlap between a lay understanding of genetics and lay intuitions about essences, we argue that, when most people are thinking about genes, they are not really thinking about genes in the complex ways that good scientists are. Combating people's essentialist biases can be a formidable challenge. Although we have identified some promising results of trying to reduce people's genetic essentialist tendencies, there is still much to learn about how these essentialist biases can be countered. It is important to help people understand genetic information so they are able make well‐informed decisions about their lives. [ABSTRACT FROM AUTHOR]

We aimed to identify obesity‐related single‐nucleotide polymorphism (SNP) loci in a Korean population and construct an obesity genetic risk score (GRS) to examine the association of the genetic predisposition to obesity with insulin resistance (IR). In total, 9675 subjects were included, and 7666 of these subjects were used for replication. A GRS was constructed using the SNP loci that overlapped in both cohort sets. The subjects showed a trend toward an increase in body mass index, waist circumference, systolic/diastolic blood pressure, homeostatic model assessment (HOMA)‐IR, HOMA‐B, and levels of insulin, triglyceride, and alanine aminotransferase across the tertiles of obesity GRS, while the adiponectin level showed a trend toward a decrease with increasing GRS. The associations between the obesity GRS and the measures of fasting insulin, HOMA‐IR, and adiponectin were significant after adjusting for confounding factors. Moreover, a significant association between obesity GRS and HOMA‐IR was observed in subjects with abdominal obesity. The present results indicate that a predisposition to obesity may affect IR in the Korean population and that abdominal fat may alter or modify the genetic effects. Furthermore, the set of obesity‐related genotypes and abdominal fat may play interactive roles in determining the risk of IR. Newly identified set of obesity‐related genotypes and abdominal fat influence the risk of insulin resistance in a Korean population. [ABSTRACT FROM AUTHOR]

Background: Individual variations of obesity‐related traits can be a consequence of dietary influence on gene variants. Methods: This cross‐sectional study aimed to evaluate (i) the effect of FTO rs9930506 on obesity and related parameters and (ii) the influence of diet on the above association in Malaysian adults. In total, 79 obese and 99 nonobese Malaysian adults were recruited. Results: In comparison with Chinese and Malays, Indians had significantly higher waist circumference (P ≤ 0.001 and P = 0.016), waist–hip ratio (P = 0.001 and P < 0.001), body fat percentage (P = 0.001 and P = 0.042), fasting insulin (P = 0.001 and P = 0.001), homeostatic model assessment‐insulin resistance (P = 0.001 and P = 0.001) and lower high‐density lipoprotein‐cholesterol levels (P < 0.001 and P < 0.001), respectively. Indians consumed significantly lower dietary cholesterol (P = 0.002), percentage energy from protein (P < 0.001) and higher fibre (P = 0.006) compared to the other two groups. Malaysian Indians expressed the highest risk allele frequency (G) of FTO rs9930506 compared to the Malays and the Chinese (P < 0.001). No significant association was found between FTO rs9930506 and obesity (dominant model). Risk allele carriers (G) consumed significantly lower vitamin E (P = 0.020) and had a higher fibre intake (P = 0.034) compared to the noncarriers (A). Gene–diet interaction analysis revealed that risk allele carriers (G) had lower high sensitivity C‐reactive protein (hsCRP) levels with higher energy from protein (≥14% day−1; P = 0.049) and higher vitamin E (≥5.4 mg day−1; P = 0.038). Conclusions: The presence of the risk allele (G) of FTO rs9930506 was not associated with an increased risk of obesity. Malaysian Indians had a significantly higher frequency of the risk allele (G). Indian participants expressed higher atherogenic phenotypes compared to Chinese and Malays. FTO rs9930506 may interact with dietary protein and vitamin E and modulate hsCRP levels. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate in vivo effects of estradiol on the regulation of hepatic inducible nitric oxide synthase (iNOS) expression in the high fat (HF) diet‐induced obesity. Also, we aimed to investigate whether activation of the extracellular signal‐regulated kinase (ERK1/2), adenosine monophosphate‐activated protein kinase (AMPK), Src kinase, and miR‐221 is involved in estradiol‐mediated regulation of iNOS in the liver of obese male Wistar rats. Male Wistar rats were fed a standard laboratory diet or a HF diet for 10 weeks. Half of HF rats were treated with estradiol intraperitoneally (40 μg/kg), whereas the other half were placebo‐treated 24 H before euthanasia. Results show that estradiol treatment of HF rats decreased hepatic iNOS mRNA (P < 0.05) and protein expression (P < 0.01), the protein levels of p65 subunit of nuclear factor κB (P < 0.05) and ERα (P < 0.05), ERK1/2 phosphorylation (P < 0.001), and ERα/Src kinase association (P < 0.05). By contrast, hepatic Src protein level (P < 0.05), AMPKα phosphorylation (P < 0.05), and miR‐221 expression (P < 0.05) were increased in HF rats after estradiol treatment. Our results indicate that estradiol in vivo regulates hepatic iNOS expression in obese rats via molecular mechanisms involving ERK1/2, AMPK, Src, and miR‐221 signaling. [ABSTRACT FROM AUTHOR]

Obesity prevalence continues to rise worldwide, posing a substantial burden on people's health. However, up to 45% of obese individuals do not suffer from cardiometabolic complications, also called the metabolically healthy obese (MHO). Concurrently, up to 30% of normal-weight individuals demonstrate cardiometabolic risk factors that are generally observed in obese individuals, the metabolically obese normal weight (MONW). Besides lifestyle, environmental factors and demographic factors, innate biological mechanisms are known to contribute to the aetiology of the MHO and MONW phenotypes, as well. Experimental studies in animal models have shown that adipose tissue expandability, fat distribution, adipogenesis, adipose tissue vascularization, inflammation and fibrosis, and mitochondrial function are the main mechanisms that uncouple adiposity from its cardiometabolic comorbidities. We reviewed current genetic association studies to expand insights into the biology of MHO/MONW phenotypes. At least four genetic loci were identified through genome-wide association studies for body fat percentage (BF%) of which the BF%-increasing allele was associated with a protective effect on glycemic and lipid outcomes. For some, this association was mediated through favourable effects on body fat distribution. Other studies that characterized the genetic susceptibility of insulin resistance found that a higher susceptibility was associated with lower overall adiposity due to less fat accumulation at hips and legs, suggesting that an impaired capacity to store fat subcutaneously or a preferential storage in the intra-abdominal cavity may be metabolically harmful. Clearly, more work remains to be done in this field, first through gene discovery and subsequently through functional follow-up of identified genes. [ABSTRACT FROM AUTHOR]

Summary: The recent global obesity epidemic is attributed to major societal and environmental changes, such as excessive energy intake and sedentary lifestyle. However, exposure to 'obesogenic' environments does not necessarily result in obesity at the individual level, as 40–75% of body mass index variation in population is attributed to genetic differences. The thrifty genotype theory posits that genetic variants promoting efficient food sequestering and optimal deposition of fat during periods of food abundance were evolutionarily advantageous for the early hunter–gatherer and were positively selected. However, the thrifty genotype is likely too simplistic and fails to provide a justification for the complex distribution of obesity predisposing gene variants and for the broad range of body mass index observed in diverse ethnic groups. This review proposes that gene pleiotropy may better account for the variability in the distribution of obesity susceptibility alleles across modern populations. We outline the lazy‐thrifty versus peppy‐thrifty genotype hypothesis and detail the body of evidence in the literature in support of this novel concept. Future population genetics and mathematical modelling studies that account for pleiotropy may further improve our understanding of the evolutionary origins of the current obesity epidemic. [ABSTRACT FROM AUTHOR]

Background Epidemiologic studies have identified risk factors associated with pulmonary hypertension and right heart failure, but causative drivers of pulmonary hypertension and right heart adaptation are not well known. We sought to leverage unbiased genetic approaches to determine clinical conditions that share genetic architecture with pulmonary pressure and right ventricular dysfunction. Methods and Results We leveraged Vanderbilt University's deidentified electronic health records and DNA biobank to identify 14 861 subjects of European ancestry who underwent at least 1 echocardiogram with available estimates of pulmonary pressure and right ventricular function. Analyses of the study were performed between 2020 and 2022. The final analytical sample included 14 861 participants (mean [SD] age, 63 [15] years and mean [SD] body mass index, 29 [7] kg/m 2 ). An unbiased phenome-wide association study identified diabetes as the most statistically significant clinical International Classifications of Diseases , Ninth Revision ( ICD-9 ) code associated with polygenic risk for increased pulmonary pressure. We validated this finding further by finding significant associations between genetic risk for diabetes and a related condition, obesity, with pulmonary pressure estimate. We then used 2-sample univariable Mendelian randomization and multivariable Mendelian randomization to show that diabetes, but not obesity, was independently associated with genetic risk for increased pulmonary pressure and decreased right ventricle load stress. Conclusions Our findings show that genetic risk for diabetes is the only significant independent causative driver of genetic risk for increased pulmonary pressure and decreased right ventricle load stress. These findings suggest that therapies targeting genetic risk for diabetes may also potentially be beneficial in treating pulmonary hypertension and right heart dysfunction.

Introduction: Observational studies have shown that body mass index (BMI) and waist-to-hip ratio (WHR) are both inversely associated with lung function, as assessed by forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). However, observational data are susceptible to confounding and reverse causation., Methods: We selected genetic instruments based on their relevant large-scale genome-wide association studies. Summary statistics of lung function and asthma came from the UK Biobank and SpiroMeta Consortium meta-analysis (n = 400,102). After examining pleiotropy and removing outliers, we applied inverse-variance weighting to estimate the causal association of BMI and BMI-adjusted WHR (WHRadjBMI) with FVC, FEV1, FEV1/FVC, and asthma. Sensitivity analyses were performed using weighted median, MR-Egger, and MRlap methods., Results: We found that BMI was inversely associated with FVC (effect estimate, -0.167; 95% confidence interval (CI), -0.203 to -0.130) and FEV1 (effect estimate, -0.111; 95%CI, -0.149 to -0.074). Higher BMI was associated with higher FEV1/FVC (effect estimate, 0.079; 95%CI, 0.049 to 0.110) but was not significantly associated with asthma. WHRadjBMI was inversely associated with FVC (effect estimate, -0.132; 95%CI, -0.180 to -0.084) but has no significant association with FEV1. Higher WHR was associated with higher FEV1/FVC (effect estimate, 0.181; 95%CI, 0.130 to 0.232) and with increased risk of asthma (effect estimate, 0.027; 95%CI, 0.001 to 0.053)., Conclusion: We found significant evidence that increased BMI is suggested to be causally related to decreased FVC and FEV1, and increased BMI-adjusted WHR could lead to lower FVC value and higher risk of asthma. Higher BMI and BMI-adjusted WHR were suggested to be causally associated with higher FEV1/FVC., (© 2023 John Wiley & Sons Ltd/University College London.)

Abstract: Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome‐wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; β = 0.81 kg/m2 per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10−11), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10–9); genetic distances at HLA were greater than at random markers (P = 1.6 × 10–46). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10–10). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Dopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hypothesized associations of DNA methylation signatures at genes modulating DA signaling with obesity features, metabolic profiles, and dietary intake. Methods: An adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened. Results: After applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p < 0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (CACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the presence or absence of abdominal obesity. Pathway analyses revealed a statistically significant contribution of the aforementioned genes to dopaminergic synapse transmission (p = 4.78E−08). Furthermore, SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p < 0.001) and carbohydrate (p < 0.001) intakes. Conclusions: The results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to investigate whether markers of endocannabinoid signaling differed between men with overweight of South Asian and white Caucasian descent.Methods: We included South Asian (n = 10) and white Caucasian (n = 10) men with overweight and prediabetes aged 35 to 50 years. Plasma samples were analyzed for endocannabinoids, their congeners, and lipids. In white adipose tissue (WAT) and skeletal muscle biopsies, mRNA expression of genes involved in the endocannabinoid system (ECS) was assessed using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Fasting lipid oxidation and glucose oxidation were determined with indirect calorimetry.Results: Compared to white Caucasians, South Asians had higher levels of plasma 2-linoleoyl glycerol (P < 0.01) and N-linoleoylethanolamine (P < 0.05). Interestingly, in skeletal muscle of South Asians, expression of cannabinoid receptors CB1 and CB2 was 10-fold lower (P < 0.001) and that of the endocannabinoid degradation enzyme fatty acid amide hydrolase 2 (FAAH2) was 5-fold lower (P < 0.001) compared to white Caucasians. Expression of genes involved in the ECS in WAT were not different between the two ethnicities. After pooling of both ethnicities, plasma 2-arachidonoylglycerol (2-AG) positively correlated with plasma triglycerides (R = 0.77, P < 0.001) and lipid oxidation (R = 0.55, P < 0.05).Conclusions: South Asian men with overweight have higher plasma 2-linoleoyl glycerol and N-linoleoylethanolamine levels and lower expression of CB receptors and the endocannabinoid degradation enzyme FAAH2 in skeletal muscle compared to white Caucasians. [ABSTRACT FROM AUTHOR]

Objective: Lifestyle factors associated with obesity may alter epigenome-regulated gene expression. Most studies examining epigenetic changes in obesity have analyzed DNA 5´-methylcytosine (5mC) in whole blood, representing a weighted average of several distantly related and regulated leukocyte classes. To examine leukocyte-specific differences associated with obesity, a pilot study examining 5mC in three distinct leukocyte types isolated from peripheral blood of women with normal weight and obesity was conducted.Methods: CD4+ T cells, CD8+ T cells, and CD16+ neutrophils were reiteratively isolated from blood, and 5mC levels were measured across >450,000 CG sites.Results: Nineteen CG sites were differentially methylated between women with obesity and with normal weight in CD4+ cells, 16 CG sites in CD8+ cells, and 0 CG sites in CD16+ neutrophils (q < 0.05). There were no common differentially methylated sites between the T-cell types. The amount of visceral adipose tissue was strongly associated with the methylation level of 79 CG sites in CD4+ cells, including 4 CG sites in CLSTN1's promoter, which, this study shows, may regulate its expression.Conclusions: The methylomes of various leukocytes respond differently to obesity and levels of visceral adipose tissue. Highly significant differentially methylated sites in CD4+ and CD8+ cells in women with obesity that have apparent biological relevance to obesity were identified. [ABSTRACT FROM AUTHOR]

Objective: Identification of novel regulators involved in adipose development is important to understand the molecular mechanism underlying obesity and associated metabolic disorders. Through isolation and analysis of a vitamin K epoxide reductase Vkorc1l1 mutant, this study aimed to disclose its function and underlying mechanism in adipose development and to obtain valuable insights regarding the mechanism of obesity.Methods: A Vkorc1l1 mutation recovered from a forward genetic screen for obesity-related loci in mice was characterized to explore its effects in gene expression, animal metabolism, and adipose development. Adipogenesis was evaluated in both Vkorc1l1 mutant stromal vascular fraction and Vkorc1l1 knockdown preadipocytes. Intracellular vitamin K2 level and the effect of vitamin K2 on adipogenesis were tested in primary preadipocytes.Results: Vkorc1l1 mutants displayed a considerably lower fat to body weight ratio, substantially decreased plasma leptin, and significantly underdeveloped white adipose tissue. Adipogenic defects related with Vkorc1l1 deficiency were observed both in vivo and in vitro. Vitamin K2 could inhibit adipogenesis in stromal vascular fraction. Increased intracellular vitamin K2 level was detected in Vkorc1l1 mutant preadipocytes.Conclusions: Vkorc1l1 promotes adipogenesis and possibly obesity. Downregulation of Vkorc1l1 increases intracellular vitamin K2 level and impedes preadipocyte differentiation. [ABSTRACT FROM AUTHOR]

The fate of mRNA is regulated by epitranscriptomic nucleotide modifications, the most abundant of which is N6‐methyladenosine (m6A). Although the pattern and distribution of m6A in mRNA is mediated by specific methyltransferases, a recent hypothesis is that specific demethylases or ‘erasers’ allow m6A to be dynamically reversed by signaling pathways. In this Review, we discuss the data in support and against this model. New insights into the function of fat mass and obesity‐associated protein (FTO), the original enzyme thought to be an m6A eraser, reveal that its physiologic target is not m6A, but instead is N6,2′‐O‐dimethyladenosine (m6Am). Another m6A demethylase, ALKBH5, appears to have functions limited to sperm development in normal mice. Overall, the majority of the data suggest that m6A is generally not reversible, although m6A may be susceptible to demethylation in pathophysiological states such as cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: No studies have focused on socioeconomic disparities in obesity within and between cohorts. Our objectives were to examine income gradients in obesity between birth‐cohorts (inter‐cohort variations) and within each birth‐cohort (intra‐cohort variations) by gender and race/ethnicity. Methods: Our sample includes 56,820 white and black adults from pooled, cross‐sectional National Health and Nutrition Examination Surveys (1971–2012). We fit a series of logistic hierarchical Age‐Period‐Cohort models to control for the effects of age and period, simultaneously. Predicted probabilities of obesity by poverty‐to‐income ratio were estimated and graphed for 5‐year cohort groups from 1901–1990. We also stratified this relationship for four gender and racial/ethnic subgroups. Results: Obesity disparities due to income were weaker for post‐World War I and II generations, specifically the mid‐1920s and the mid‐1940s to 1950s cohorts, than for other cohorts. In contrast, we found greater income gradients in obesity among cohorts from the 1930s to mid‐1940s and mid‐1960s to 1970s. Moreover, obesity disparities due to income across cohorts vary markedly by gender and race/ethnicity. White women with higher income consistently exhibited a lower likelihood of obesity than those with lower income since early 1900s cohorts; whereas, black men with higher income exhibited higher risks of obesity than those with lower income in most cohorts. Conclusions: Our findings suggest that strategies that address race and/or gender inequalities in obesity should be cognizant of significant historical factors that may be unique to cohorts. Period‐based approaches that ignore life‐course experiences captured in significant cohort‐based experiences may limit the utility of policies and interventions. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Results of published studies on the association between sedentary behavior (SB) and obesity are inconsistent, possibly due to reliance on subjective measures of SB and inappropriate measures of obesity. The aim of this study was to examine the relationship between objectively measured SB and criterion‐measured obesity among adults. Methods: A total of 2284 adults (≥18 years) from the 2003 to 2004 National Health and Nutrition Examination Survey were included in the analysis. The participants were categorized into tertiles of SB time measured by accelerometry. Obesity was determined using body fat percentage measured by dual‐energy X‐ray absorptiometry. Results: Increased SB was significantly associated with obesity when controlling for covariates related to demographics, health behaviors, energy intake, and physical activity (P for trends = .025). Conclusions: This finding suggests that avoiding SB may be beneficial for lowering the risk of obesity in adults. [ABSTRACT FROM AUTHOR]

Summary: The Pakistani population is extensively diverse, indicating a genetic admixture of European and Central/West Asian migrants with indigenous South Asian gene pools. Pakistanis are organized in different ethnicities/castes based on cultural, linguistic and geographical origin. While Pakistan is facing a rapid nutritional transition, the rising prevalence of obesity is driving a growing burden of health complications and mortality. This represents a unique opportunity for the research community to study the interplay between obesogenic environmental changes and obesity predisposing genes in the time frame of one generation. This review recapitulates the ancestral origins of Pakistani population, the societal determinants of the rise in obesity and its governmental management. We describe the contribution of syndromic, monogenic non‐syndromic and polygenic obesity genes identified in the Pakistani population. We then discuss the utility of gene identification approaches based on large consanguineous families and original gene × environment interaction study designs in discovering new obesity genes and causal pathways. Elucidation of the genetic basis of obesity in the Pakistani population may result in improved methods of obesity prevention and treatment globally. [ABSTRACT FROM AUTHOR]

Objective: Consanguinity has been instrumental in the elucidation of many Mendelian genetic diseases. Here, the unique advantage of consanguineous populations was considered in the quest for genes causing obesity.Methods: PubMed was searched for articles relevant to consanguinity and obesity published between 1995 and 2016. Some earlier articles of interest were also consulted.Results: Although obesity is the most heritable disorder, even in outbred populations, only 2% to 5% of severe obesity cases have so far been proven to be caused by single gene mutations. In some highly consanguineous populations, a remarkably higher proportion of obesity cases because of known and novel monogenic variants has been identified (up to 30%).Conclusions: Combining the power conferred by consanguinity with current large-capacity sequencing techniques should bring new genetic factors and molecular mechanisms to the fore, unveiling a large part of the yet-elusive neurohumoral circuitry involved in the regulation of energy homeostasis and appetite. Importantly, the undertaking of such initiatives is destined to unfold novel targets for the development of precision medicine relevant to different forms of obesity. [ABSTRACT FROM AUTHOR]