Diabesity, the concurrent occurrence of obesity and type-2 diabetes mellitus (T2DM), represents a pressing global health challenge characterized by intricate pathophysiological mechanisms and a wide range of associated comorbidities. Central to its development are insulin resistance, metabolic syndrome, and chronic low-grade inflammation mediated by dysregulated adipokine secretion and systemic metabolic dysfunction. These mechanisms underpin the progression of diabesity and its complications, including cardiovascular disease and hypertension. Management strategies encompass lifestyle interventions focusing on tailored dietary modifications and structured physical activity, pharmacological treatments targeting both glycemic control and weight loss, and surgical interventions such as bariatric surgery, which have demonstrated efficacy in achieving durable outcomes. Clinical trials and meta-analyses underscore the comparative advantages of different treatment modalities in terms of efficacy, safety, and sustainability. Moreover, long-term follow-up studies emphasize the critical need for sustained multidisciplinary interventions to prevent relapse and enhance patient outcomes. Future advancements in management include exploring precision medicine approaches that integrate individual metabolic profiles, lifestyle factors, and emerging therapeutic innovations. A multidisciplinary approach combining advanced therapeutic strategies and patient-centered care remains pivotal for optimizing management and improving prognoses for individuals with diabesity. This review highlights the complex interplay between obesity and T2DM, offering comprehensive insights into their pathophysiology, clinical presentation, and management paradigms.

Mitochondria play a key role in lipid metabolism, and mitochondrial DNA (mtDNA) mutations are thus considered to affect obesity susceptibility by altering oxidative phosphorylation and mitochondrial function. In this study, we investigate mtDNA variants that may affect obesity risk in 2877 Han Chinese individuals from 3 independent populations. The association analysis of 16 basal mtDNA haplogroups with body mass index, waist circumference, and waist-to-hip ratio reveals that only haplogroup M7 is significantly negatively correlated with all three adiposity-related anthropometric traits in the overall cohort, verified by the analysis of a single population, i.e., the Zhengzhou population. Furthermore, subhaplogroup analysis suggests that M7b1a1 is the most likely haplogroup associated with a decreased obesity risk, and the variation T12811C (causing Y159H in ND5) harbored in M7b1a1 may be the most likely candidate for altering the mitochondrial function. Specifically, we find that proportionally more nonsynonymous mutations accumulate in M7b1a1 carriers, indicating that M7b1a1 is either under positive selection or subject to a relaxation of selective constraints. We also find that nuclear variants, especially in DACT2 and PIEZO1, may functionally interact with M7b1a1.

This study examines the impact of obesity on the current health and academic performance of college students, with potential long-term implications for their overall well-being. Using survey data from 300 students at a university in the Arab Gulf of Oman, the study finds that over 27% of students are classified as overweight or obese. The analysis reveals a significant negative relationship between obesity and academic performance, with obese students showing a 6.6% decrease in academic grades compared to their peers of healthy weight. The findings suggest that the likelihood of earning lower academic grades is 2.54 times higher among obese students than those with normal weight. Additionally, the study indicates that obese students face an 8.5% higher burden of obesity-related health issues and are 5.77 times more likely to develop such conditions compared to normal-weight students. These results highlight that obesity affects both academic achievement and health, with potential long-term consequences for students' well-being. To address these issues, educational institutions and communities should prioritize promoting healthy lifestyles, including proper nutrition and weight management support.

There is large variation in the individual risk of developing obesity-associated comorbidities. While obesity is highly prevalent in Mexico, data on the extent and heterogeneity of its associated co-morbidities is lacking. Hereby, we estimated the prevalence of different obesity-associated comorbidities, and how they have changed over 15 years.

We gathered data from different editions of nationally representative health and nutrition surveys (ENSANUT) from 2006 to 2022. The prevalence of obesity and the coexistence with diabetes, dyslipidemia, hypertension, depression, and impaired mobility, which are outcomes used in the Edmonton Obesity Staging System (EOSS) which assesses three dimensions (medical, mental, and functional) across five incremental severity stages, by sex and age groups were estimated across all included surveys. Metabolically healthy obesity was defined as the absence of diabetes, dyslipidemia and hypertension.

20758 participants were analyzed. Mean BMI increased progressively at all ages from 30.2 to 31.0 across survey rounds. Depression and impaired mobility were highly prevalent even among metabolically healthy obese individuals. While most people with obesity had at least one detectable abnormality, there was large heterogeneity in the presented comorbidities. The most prevalent EOSS categories were stage 2 for the medical dimension (90.1%), and stage 1 for the functional and mental dimensions (75.1% and 62.9%, respectively). The prevalence of obesity-related comorbidities increased with age but was similar across all surveys. In both sexes, metabolically healthy obesity was less likely as age and BMI increased.

The prevalence of obesity comorbidities has been stable over time in Mexico but increases with age. The rising prevalence of obesity and the ageing of the population will cause additional burdens to the population and the health system.

Body mass index (BMI) has been implicated in various cardiovascular conditions, but its association with peripheral artery disease (PAD) in both real-world and genetic studies have been contentious and debated.

This study enrolled 6707 individuals from the National Health and Nutrition Examination Survey database to investigate the association between BMI and the risk of PAD. The weighted logistic regression, restricted cubic spline, and subgroup analysis were performed using real-world data. Mendelian randomization study was conducted using genetic data from the Genome-Wide Association Study. The inverse variance weighted method was used as the primary analysis approach, and a sensitivity analysis was conducted to identify pleiotropy and heterogeneity bias.

Individuals with PAD had higher mean BMI values compared to those without PAD (28.82 ± 5.87 and 28.31 ± 5.42, P = 0.007). For the categorical variable of BMI, individuals in obesity class 2 (odds ratio [OR] = 1.532, 95% CI = 1.082-2.169; P = 0.013) and obesity class 3 (OR = 2.479, 95% CI = 1.515-4.056; P < 0.001) had a higher risk of PAD analyzed by weighted logistic regression. Subgroup analysis revealed that the association between BMI and PAD persisted. Given that a higher BMI is associated with PAD, we selected obesity for Mendelian randomization analysis and observed that obesity had a relationship with PAD (inverse variance weight: OR = 1.194, 95% CI = 1.099-1.296; P < 0.001). The reliable findings were validated by sensitive analysis (all P > 0.05).

BMI is a robust risk factor for PAD. A higher BMI (especially ≥35 kg/m2) is associated with an increased risk of developing PAD. Meanwhile, there is a causal relationship between obesity and PAD. Interventions are necessary for targeted obesity prevention and management strategies for PAD.

Nutritional status disorders have the most significant impact on the development of cardiovascular and oncologic diseases; therefore, the interest in the study of palm oil as among the leading components of nutrition has been increasing. The data examined in this review were sourced from the Scopus, SCIE (Web of Science), PubMed and PubMed Central, MEDLINE, CAPlus/SciFinder, and Embase databases; experts in the field; bibliographies; and abstracts from review analyses from the past 15 years. This review summarizes recent research data focusing on the quantitative and qualitative composition of nutrition of modern humans; concepts of the relationship between high-fat diets and disorders of insulin functioning and transport and metabolism of fatty acids; analyses of data regarding the palmitic acid (16:0) to oleic acid (18:1) ratio; and the effect of diet based on palm oil consumption on cardiovascular risk factors and lipid and lipoprotein levels. Several studies suggest a potential vector contributing to the transmission of maternal, high-fat-diet-induced, addictive-like behaviors and obesogenic phenotypes across generations. The relationship between cholesterol accumulation in lysosomes that may lead to lysosome dysfunction and inhibition of the autophagy process is analyzed, as is the progression of inflammatory diseases, atherosclerosis, nonalcoholic liver inflammation, and obesity with associated complications. Data are discussed from analyses of differences between rodent models and human population studies in the investigated different effects of palm oil consumption as a high-fat diet component. A conclusion is reached that the results cannot be generalized in human population studies because no similar effects were observed. Although there are numerous published reports, more studies are necessary to elucidate the complex regulatory mechanisms in digestive and nutrition processes, because there are great differences in lipoprotein profiles between rodents and humans, which makes it difficult to reproduce the pathology of many diseases caused by different types of the high-fat diet.

Obesity plays a crucial role in the development of metabolic disorders including diabetes, coronary and renal diseases. There are several factors involved in the pathology of obesity, including chronic inflammation and exposure to environmental contaminants. Recently, the cholinergic co-hydrolyzing enzyme BChE has been associated with clinical conditions such as diabetes and obesity. This study aims to investigate the levels of BChE and inflammatory markers in the serum, as well as the association between two specific BCHE gene variants (rs1803274 and rs3495) and the risk of obesity in the Pakistani population.

The study recruited 350 people with obesity and 200 volunteers with no obesity. Proinflammatory cytokines (TNF-α, IL-6, and IL-1β) levels were quantified using ELISA kits, while the analysis of BCHE gene SNPs rs1803274 (K-variant) and rs3495 was conducted using the tetra-primer amplification refractory mutation-PCR (tetra-ARM-PCR) and PCR-restriction fragment length polymorphism (RFLP) methods, respectively. Additionally, clinico-pathological parameters HDL, LDL, BMI, Homa-IR, insulin, glucose, blood pressure was also assessed in subjects of current study.

Results showed significantly higher levels of BChE, TNF-α, IL-1β, and IL-6 in the obesity group compared to the group without obesity. Furthermore, the obesity group exhibited higher blood pressure and LDL levels, as well as lower HDL levels when compared to group without obesity. Logistic regression analysis revealed a relationship between obesity and higher BChE activity, blood pressure, LDL, and lower HDL levels. The study also found a statistically significant association between the BCHE gene SNPs rs1803274 (K-variant) and rs3495 and the risk of obesity (OR = 2.01; CI = 1.21-3.33; p = 0.0063; OR = 1.80; CI = 1.09-2.96, respectively).

In conclusion, the study suggests that BChE and inflammatory cytokines play a significant role in the development and pathogenesis of obesity and can also act as good diagnostic biomarkers for obesity and its related metabolic disorders.

Obesity is a complex heterogeneous disease often associated with dysfunctional eating behavior patterns. Oxytocin (OT) is a neurohormone involved in the regulation of energy metabolism and eating behavior. The aim of the present study was to evaluate in a population of patients with obesity circulating levels of OT and dysfunctional eating behaviors in relation to anthropometric, hormonal and metabolic parameters.

A prospective, observational, single-center study was conducted at the Center of High Specialization for the Care of Obesity of Sapienza University of Rome. Adult subjects with body mass index (BMI) ≥ 30 kg/m2 were recruited. Body impedance assessment (BIA), biochemical and hormonal parameters, plasma OT concentration analysis and the Eating Behaviors Assessment for Obesity (EBA-O) questionnaire were evaluated.

A total of 21 patients, 16 females and 5 males, with a mean age of 45.7 ± 15.1 years, mean BMI of 40.89 ± 8.02 kg/m2 and plasma OT concentration of 1365.61 ± 438.03 pg/mL were recruited. The dysfunctional eating behavior traits investigated by the EBA-O appear significantly associated with metabolic derangements. In particular, night eating is associated with alterations in lipid metabolism (p < 0.01). Circulating OT correlates positively with BMI (r = 0,43; p < 0.05), and Hepatic Steatosis Index (HIS) (r = 0.46; p < 0.05), while its role in subjects with obesity and alterations in glucose metabolism is less clear. Interestingly, circulating OT levels < 1312.55 pg/mL may be predictive of food addiction (100% sensitivity; 62.5% specificity).

Despite the need for larger studies to confirm their validity, the clinical utility of the EBA-O and circulating OT in identifying dysfunctional eating behaviors appears promising.

Numerous studies have shown a link between circadian rhythms disruptions and a higher risk of obesity. This article aims to conduct an extensive bibliometric analysis to deepen our understanding of the relationship between circadian rhythms and obesity.

The literature related to the circadian rhythm of obesity, published from the inception of the Web of Science Core Collection (WoSCC) until June 30, 2024, was extracted from the WoSCC databases (SCIE, SSCI, ESCI). Using CiteSpace, Vosviewer, WPS, and other software, this paper examines the publication trends, including the number of papers, countries/regions, institutions, authors, journals, references, and keywords.

A total of 2,870 articles were included in this analysis, revealing a consistent year by year increase in research on the circadian rhythm of obesity. These publications originate from 460 institutions in 88 countries. Among the authors analysis, Garaulet, Marta was the most prolific, and Turek FW was the most co-cited. Proceedings of the National Academy of Sciences of the United States of America emerged as the journal with the highest number of publications, and American Journal of Physiology had the highest centrality. The most frequently used keywords were "obesity," "circadian rhythm," "circadian clock," "metabolic syndrome," "metabolism." Additionally, research areas involving intermittent fasting, restricted feeding, and gut microbiota were rapidly developing and represented the forefront of research on circadian rhythms and obesity.

Our study demonstrates that research on circadian rhythms in obesity has been rapidly expanding, with increasingly in-depth exploration of the topic. It is recommended to strengthen cooperation between countries and institutions to jointly promote research in this field. The gene expression of obesity is an early hotspot in the study of circadian rhythm and obesity, and emerging research areas such as intermittent fasting, restricted feeding, endothelial nitric oxide synthase and gut microbiota will become significant hotspots and trends in the field of circadian rhythm and obesity. These findings provide researchers critical directions for future studies and may have significant implications for clinical practice and public health policy.

The cerebellum is one of the major central nervous structures consistently altered in obesity. Its role in higher cognitive function, parts of which are affected by obesity, is mediated through projections to and from the cerebral cortex. We therefore investigated the relationship between body mass index (BMI) and cerebellocerebral connectivity.

We utilized the Human Connectome Project's Young Adults dataset, including functional magnetic resonance imaging (fMRI) and behavioral data, to perform connectome-based predictive modeling (CPM) restricted to cerebellocerebral connectivity of resting-state fMRI and task-based fMRI. We developed a Python-based open-source framework to perform CPM, a data-driven technique with built-in cross-validation to establish brain-behavior relationships. Significance was assessed with permutation analysis.

We found that (i) cerebellocerebral connectivity predicted BMI, (ii) task-general cerebellocerebral connectivity predicted BMI more reliably than resting-state fMRI and individual task-based fMRI separately, (iii) predictive networks derived this way overlapped with established functional brain networks (namely, frontoparietal networks, the somatomotor network, the salience network, and the default mode network), and (iv) we found there was an inverse overlap between networks predictive of BMI and networks predictive of cognitive measures adversely affected by overweight/obesity.

Our results suggest obesity-specific alterations in cerebellocerebral connectivity, specifically with regard to task execution. With brain areas and brain networks relevant to task performance implicated, these alterations seem to reflect a neurobiological substrate for task performance adversely affected by obesity.

The Planetary Health Diet, proposed by the EAT-Lancet Commission, seeks to promote a sustainable and healthy diet for both humans and the environment. However, few studies have investigated relationships between the Planetary Health Diet and the genetic pathway of obesity. The aim of this study was to assess whether adherence to a Planetary Health Diet Index (PHDI) mediated or moderated the genetic susceptibility to obesity.

Participants were 7,037 adults (57% females, aged 55.6 ± 7.7) from the Quebec CARTaGENE Biobank. We constructed a primary polygenic risk score (PRS-Khera) for body mass index (BMI) comprised of ~ 2 million SNPs and utilized a secondary 97 SNPs polygenic risk score (PRS-Locke) for sensitivity analyses. The PHDI was based on 16 food groups. General linear models were conducted to assess main effect associations between the PRSs, the Planetary Health Diet Index (PHDI), and the individual food groups that comprise the PHDI on obesity outcomes. Causal mediation analyses (CMA) were used to evaluate mediation and interaction effects. All models were adjusted for age, sex, genetic ancestry, socio-demographic, and lifestyle variables, including those associated with dietary habits.

The overall PHDI was inversely associated with BMI (β = - 0.11, 95% confidence interval (CI): - 0.13, - 0.09), waist circumference (WC) (β = - 0.12, 95% CI: - 0.14, - 0.10), and body fat % (β = - 0.10, 95% CI: - 0.12, - 0.08) for all participants, but did not mediate or moderate obesity polygenic risk. Associations between the PRS-Khera and obesity outcomes in all participants were partly mediated by the intake of red meat (mediation effect BMI: 1.72%, p = 0.01; WC: 2.22%, p = 0.01; body fat %: 2.14%, p = 0.01). Moreover, among males, whole grains intake partly mediated the association between the PRS-Khera and outcomes cross-sectionally (BMI: 1.28%, p = 0.03; WC: 1.71%, p = 0.02; body fat %: 2.19%, p = 0.02) and longitudinally (BMI: 3.80%, p = 0.02; WC: 7.38%, p = 0.04), but some observations were attenuated upon correction for multiple comparisons.

PHDI adherence was associated with a lower BMI, WC, and body fat % and genetic susceptibility to obesity was partly mediated by the intake of red meat and whole grains. Some components of a plant-based diet could be implicated in mechanisms underlying genetic susceptibility to obesity.

Obesity and atherogenesis are two highly prevalent pathological processes that are closely related to the increase in cardiometabolic diseases. The aim of this study is to assess the relationship between obesity and two parameters that measure the risk of atherogenesis: atherogenic dyslipidaemia (AD) and the lipid triad (TL).

Descriptive and cross-sectional study in 418,343 Spanish workers in which the possible association between AD and TL with different scales of overweight and obesity such as body mass index (BMI), waist/height index, Clínica Universitaria de Navarra Body Adiposity Estimator (CUN BAE), relative fat mass (RFM), Palafolls and Deuremberg formulas, body surface index (BSI), normalized weight-adjusted index (NWAI) and body roundness index (BRI) was assessed.

The values of all overweight-obesity scales are higher in people with AD and LBP and the prevalence of AD and LBP increases as the values of these overweight-obesity scales increase. The overweight-obesity scales that best predict the occurrence of AD are Deuremberg and CUN BAE (AUC 0.813 and 0.811 in men and 0.810 and 0.802 in women) while for TL they are also Deuremberg and CUN BAE (AUC 0.793 and 0.786 in men and 0.802 and 0.786 in women).

The different scales that assess excess weight, especially those that predict body fat such as the Deuremberg formula and CUN BAE, are good predictors of AD and LD.

To explore whether radiomics analysis of pericoronary adipose tissue (PCAT) captured by coronary computed tomography angiography (CCTA) could discriminate unstable angina (UA) from stable angina (SA).

In this single-center retrospective case-control study, coronary CT images and clinical data from 240 angina patients were collected and analyzed. Patients with unstable angina (n = 120) were well-matched with those having stable angina (n = 120). All patients were randomly divided into training (70%) and testing (30%) datasets. Automatic segmentation was performed on the pericoronary adipose tissue surrounding the proximal segments of the left anterior descending artery (LAD), left circumflex coronary artery (LCX), and right coronary artery (RCA). Corresponding radiomic features were extracted and selected, and the fat attenuation index (FAI) for these three vessels was quantified. Machine learning techniques were employed to construct the FAI and radiomic models. Multivariate logistic regression analysis was used to identify the most relevant clinical features, which were then combined with radiomic features to create clinical and integrated models. The performance of different models was compared in terms of area under the curve (AUC), calibration, clinical utility, and sensitivity.

In both training and validation cohorts, the integrated model (AUC = 0.87, 0.74) demonstrated superior discriminatory ability compared to the FAI model (AUC = 0.68, 0.51), clinical feature model (AUC = 0.84, 0.67), and radiomic model (AUC = 0.85, 0.73). The nomogram derived from the combined radiomic and clinical features exhibited excellent performance in diagnosing and predicting unstable angina. Calibration curves showed good fit for all four machine learning models. Decision curve analysis indicated that the integrated model provided better clinical benefit than the other three models.

CCTA-based radiomics signature of PCAT is better than the FAI model in identifying unstable angina and stable angina. The integrated model constructed by combining radiomics and clinical features could further improve the diagnosis and differentiation ability of unstable angina.

Epigenetic processes play a crucial role in mediating the impact of environmental energetic challenges, from overconsumption to starvation. Over-nutrition of energy-dense foods and sedentary lifestyles contribute to the development of obesity, characterized by excessive fat storage and impaired metabolic signaling, stemming from disrupted brain signaling. Conversely, dieting and physical activity facilitate body weight rebalancing and trigger adaptive neural responses. These adaptations involve the upregulation of neurogenesis, synaptic plasticity and optimized brain function and energy homeostasis, balanced hormone signaling, normal metabolism, and reduced inflammation. The transition of the brain from a maladaptive to an adaptive state is partially guided by epigenetic mechanisms. While epigenetic mechanisms underlying obesity-related brain changes have been described, their role in mediating the reversal of maladaptation/obesity through lifestyle interventions remains less explored. This review focuses on elucidating epigenetic mechanisms involved in hypothalamic adaptations induced by lifestyle interventions. Given that lifestyle interventions are widely prescribed and accessible approaches for weight loss and maintenance, it is our challenge to uncover epigenetic mechanisms moderating these hypothalamic-functional beneficial changes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered multifactorial with a number of predisposing gene polymorphisms known.

The occurrence of MASLD in 7 and 10 year old siblings, one without classical risk factors and one with type 2 diabetes suggested a monogenic etiology and prompted next-generation sequencing. Exome sequencing was performed in the proband, both parents and both siblings. The impact of a likely disease-causing DNA variant was assessed on the transcript and protein level.

Two siblings have hepatomegaly, elevated serum transaminase activity, and steatosis and harbor a homozygous DECR1 splice-site variant, c.330+3A>T. The variant caused DECR1 transcript decay. Immunostaining demonstrated lack of DECR1 in patient liver.

These patients may represent the first individuals with DECR1 deficiency, then defining within MASLD an autosomal-recessive entity, well corresponding to the reported steatotic liver disease in Decr1 knockout mice. DECR1 may need to be considered in the genetic work-up of MASLD.

Genetic testing is increasingly used in clinical practice to provide personalized information and recommendations about health risks and lifestyle habits at a relatively low cost. Research on the effectiveness of nutrigenomics-guided lifestyle interventions is growing. A scoping review approach was adopted to identify pertinent published studies on nutrigenomics-guided intervention programmes from 2007 to 2023. The review shows that despite the growing interest in nutrigenomics-guided lifestyle interventions, there are still few empirically supported studies, primarily based on developed countries. Furthermore, the findings on the impact of personalised genetic advice are mixed, leaving the field unclear. Existing studies have some empirical strength, contributing to further understanding of the relationship between food and gene expression. However, some limitations that affect the robustness of findings exist, such as a small sample size, insufficient monitoring of the data collection process, and a short follow-up period. Future research needs to address reliability concerns and provide more robust practical evidence.

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

Breastfeeding may interact with other risk factors and have a combined influence on child growth. This systematic review aimed to examine the interaction between genetic factors and breastfeeding and how their combination is associated with children weight status. Four databases were searched until August 2024, and 8 eligible studies were identified. The fat mass and obesity associated (FTO) and peroxisome proliferator-activated receptor γ2 (PPARG2) genes were the most examined genes. Although the results of interactions between breastfeeding and genetics factors on children's weight status were inconsistent, some of studies reported that breastfeeding or exclusive breastfeeding attenuated the disadvantageous association between the risk alleles of the genes (higher obesity-specific genetic risk score for a multiple-gene study) and overdevelopment of children's body weight. These findings support the WHO recommendations for prolonged breastfeeding and further suggest breastfeeding interventions to prevent childhood obesity may be more effective in populations with a disadvantageous genetic predisposition. This review was registered in PROSPERO as CRD42023448365.

Existing observational studies examining the effect of body fat on the risk of Parkinson disease (PD) have yielded inconsistent results. We aimed to investigate this causal relationship at the genetic level.

We employed two-sample Mendelian randomization (TSMR) to investigate the causal effects of body fat on PD, with multiple sex-specific body fat measures being involved. We performed Bayesian colocalization analysis and cross-trait meta-analysis to reveal pleiotropic genomic loci shared between body mass index (BMI) and PD. Finally, we used the MAGMA tool to perform tissue enrichment analysis of the genome-wide association study hits of BMI.

TSMR analysis suggests that except waist circumference, higher measures of body fatness are associated with a decreased risk of PD, including BMI (OR: 0.83), body fat percentage (OR: 0.69), body fat mass (OR: 0.77), and hip circumference (OR: 0.83). The observed effects were slightly more pronounced in females than males. Colocalization analysis highlighted two colocalized regions (chromosome 3p25.3 and chromosome 17p12) shared by BMI and PD and pointed to some genes as possible players, including SRGAP3, MTMR14, and ADORA2B. Cross-trait meta-analysis successfully identified 10 novel genomic loci, involving genes of TOX3 and MAP4K4. Tissue enrichment analysis showed that BMI-associated genetic variants were enriched in multiple brain tissues.

We found that nonabdominal body fatness exerts a robust protective effect against PD. Our colocalization analysis and cross-trait meta-analysis identified pleiotropic genetic variation shared between BMI and PD, providing new clues for understanding the association between body fat and PD.

Gene-environment interaction studies are emerging as a promising tool to shed light on the reasons for the rapid increase in excess body weight (overweight and obesity). We aimed to investigate the influence of several polymorphisms on excess weight in Spanish children according to a short- and long-term exposure to bisphenols and parabens, combining individual approach with the joint effect of them. This case-control study included 144 controls and 98 cases children aged 3-12 years. Thirty SNPs in genes involved in obesity-related pathways, xenobiotic metabolism and hormone systems were genotyped using the GSA microchip technology and qPCRs with Taqman® probes. Levels of bisphenols and parabens in urine and hair were used to assess short- and long-term exposure, respectively, via UHPLC-MS/MS system. LEPR rs9436303 was identified as a relevant risk variant for excess weight (ORDom:AAvsAG+GG=2.65, p<0.001), and this effect persisted across exposure-stratified models. For long-term exposure, GPX1 rs1050450 was associated with increased excess weight at low single paraben exposure (ORGvsA=2.00, p=0.028, p-interaction=0.016), whereas LEPR rs1137101 exhibited a protective function at high co-exposure (ORDom:AAvsAG+GG=0.17, p=0.007, p-interaction=0.043). ESR2 rs3020450 (ORDom:GGvsAG+AA=5.17, p=0.020, p-interaction=0.028) and CYP2C19 rs4244285 (ORDom:GGvsAG+AA=3.54, p=0.039, p-interaction=0.285) were identified as predisposing variants at low and high co-exposure, respectively. In short-term exposure, higher odds were observed for INSIG2 rs7566605 at high bisphenol exposure (ORCvsG=2.97, p=0.035, p-interaction=0.017) and for GSTP1 rs1695 at low levels (ORDom:AAvsAG+GG=5.38, p=0.016, p-interaction=0.016). At low and medium co-exposure, SH2B1 rs7498665 (ORAvsG=0.17, p=0.015, p-interaction=0.085) and MC4R rs17782313 (ORAvsG=0.10, p=0.023, p-interaction=0.045) displayed a protective effect, whereas ESR2 rs3020450 maintained its contributing role (ORGvsA=3.12, p=0.030, p-interaction=0.010). Our findings demonstrate for the first time that understanding the genetic variation in excess weight and how the level of exposure to bisphenols and parabens might interact with it, is crucial for a more in-depth comprehension of the complex polygenic and multifactorial aetiology of overweight and obesity.

Obesity is a complex chronic disease that affects millions of people worldwide. There is still significant stigma associated with it, which can lead to discrimination and create additional barriers for people who are already in treatment. On the other hand, it is noted that it can have serious implications for health and predisposition to noncommunicable chronic diseases. In this sense, the objective of this study was to carry out a narrative review involving all current elements for understanding, prevention, treatment, and debate of stigmas related to obesity. A search was conducted in 2024 for original articles, randomized or nonrandomized clinical trials, systematic reviews, meta-analyses, and guidelines in the following databases: Pubmed, Scielo, Web of Science, CrossRef, and Google Scholar. The publication period was from 2014 to 2024. Obesity is influenced by a complex combination of genetic, environmental, and psychological factors. It is encouraging to see that various emerging points have been identified across different fields such as histology, physiology, genetics, weight loss, and public policy. These obesity areas certainly warrant attention and future studies. Researchers can delve into these topics to deepen their understanding and potentially uncover novel insights. The management should be multifactorial and individualized for each patient. Public policies also play a crucial role in combating obesity, including health promotion, prevention of excessive weight gain, early diagnosis, and proper care of patients. It is crucial that society begins to see the disease as an extremely complex element and not as a moral failure or lack of willpower. This requires a change in the way people talk about obesity, as well as practices that support people instead of stigmatizing them. Obesity does not have a specific address, color, or race. It belongs to everyone and should be regarded as a global public health problem.

Obesity is as an important risk factor for chronic diseases. Metabolically healthy obesity (MHO) is considered a benign state. The association between metabolic health and obesity categories and cancer risk remains unclear. This study aimed to investigate the relationship between metabolic health status combined with obesity phenotypes and the risk of cancer.

Data from 91,834 participants in the Kailuan cohort were analyzed, excluding individuals with a body mass index (BMI) < 18.5 kg/m² and those with a history of cancer. Obesity phenotypes were classified based on BMI and waist circumference (WC) combined with metabolic health status, resulting in six phenotypes. Cox proportional hazard regression models were used to assess the association between metabolic health and obesity phenotypes with cancer risk and all-cause mortality.

The prevalence of metabolically healthy obesity and metabolically unhealthy obesity defined by BMI was 6.86% and 12.18%, while that defined by WC was 20.79% and 25.76%, respectively. Compared to metabolically healthy participants, individuals with an unhealthy metabolic status had a significantly higher risk of cancer (HR, 1.09; 95% CI, 1.03-1.15; p=0.004). The hazard ratios for cancer were 1.19, 1.23, 1.20, and 1.55 for individuals with one, two, three, and four metabolic disorders, respectively. Among those classified as metabolically unhealthy, both overweight and obesity were associated with a protective effect on cancer risk (HR, 0.88; 95% CI, 0.80-0.96; p=0.006 for overweight; HR, 0.87; 95% CI, 0.78-0.97; p=0.010 for obesity). However, abdominal obesity significantly increased cancer risk in both metabolically healthy and unhealthy participants. In subgroup analysis, simple obesity showed a protective trend against cancer in those with respiratory cancers, while abdominal obesity consistently posed a risk for various cancer types.

Metabolically unhealthy status and abdominal obesity are risk factors for cancer and all-cause mortality, whereas simple obesity offers protective effects against cancer and all-cause mortality in metabolically unhealthy individuals. These findings suggest that maintaining metabolic health and reducing the metabolic risks associated with abdominal obesity should be key targets for cancer prevention.

Chronic wounds pose a significant challenge to healthcare. Stemming from impaired wound healing, the consequences can be severe, ranging from amputation to mortality. This comprehensive review explores the multifaceted impact of chronic wounds in medicine and the roles that diet and nutritional pathologies play in the wound-healing process. It has been well established that an adequate diet is crucial to proper wound healing. Nutrients such as vitamin D, zinc, and amino acids play significant roles in cellular regeneration, immune functioning, and collagen synthesis and processing. Additionally, this review discusses how patients with chronic conditions like diabetes, obesity, and nutritional deficiencies result in the formation of chronic wounds. By integrating current research findings, this review highlights the significant impact of the genetic make-up of an individual on the risk of developing chronic wounds and the necessity for adequate personalized dietary interventions. Addressing the nutritional needs of individuals, especially those with chronic conditions, is essential for improving wound outcomes and overall patient care. With new developments in the field of genomics, there are unprecedented opportunities to develop targeted interventions that can precisely address the unique metabolic needs of individuals suffering from chronic wounds, thereby enhancing treatment effectiveness and patient outcomes.

Protium heptaphyllum (P. heptaphyllum), popularly known as "almacega" or "white pitch", is widely used in folk medicine due to its antioxidant, anti-inflammatory and healing properties, attributed to its richness in flavonoids and terpenes. Therefore, this study aimed to evaluate the effects of treatment for 28 days with liposomes containing P. heptaphyllum leaf extract in obese animals. Male Wistar rats, subjected to a hypercaloric diet for 8 weeks to induce obesity (hypercaloric chow and water enriched with 30% sucrose, ad libitum), were treated with the plant formulation (1 mg kg-1day-1, via gavage) for 28 days. The study investigated morphological, metabolic, redox state, immunological and histological parameters in adipose and liver tissue. Rats were divided into four groups: control (C), liposomes with extract (H), obese (O) and obese treated with liposomes containing extract (OH). The results indicated that the obese group (O) presented weight gain, hepatic steatosis and alterations in metabolic and inflammatory parameters. However, treatment with liposomes (OH) reduced glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), creatinine and the lipid profile. In adipose tissue, the OH group showed decreased superoxide dismutase (SOD) activity and increased glutathione S-transferase (GST) activity, in contrast to the effects observed in liver GST. In the analysis of thiobarbituric-acid-reactive substances (TBARS), it was possible to observe an increase in all groups in adipose tissue and in group O in liver tissue, in addition to a reduction in TBARS in group OH in the liver, indicating modulation of oxidative stress. The treatment also increased the concentration of IL-10 and IL-17 in the liver and decreased that of IL-6 in adipose tissue. After 28 days of treatment, these results point to the therapeutic potential of treatment with P. heptaphyllum, not necessarily only against obesity, but also an effect per se of the liposomes, possibly due to the high concentration of flavonoids present in the plant extract.

The hypothalamus, composed of several nuclei, is essential for maintaining our body's homeostasis. The arcuate nucleus (ARC), located in the mediobasal hypothalamus, contains neuronal populations with eminent roles in energy and glucose homeostasis as well as reproduction. These neuronal populations are of great interest for translational research. To fulfill this promise, we used a robotic cell culture platform to provide a scalable and chemically defined approach for differentiating human pluripotent stem cells (hPSCs) into pro-opiomelanocortin (POMC), somatostatin (SST), tyrosine hydroxylase (TH) and gonadotropin-releasing hormone (GnRH) neuronal subpopulations with an ARC-like signature. This robust approach is reproducible across several distinct hPSC lines and exhibits a stepwise induction of key ventral diencephalon and ARC markers in transcriptomic profiling experiments. This is further corroborated by direct comparison to human fetal hypothalamus, and the enriched expression of genes implicated in obesity and type 2 diabetes (T2D). Genome-wide chromatin accessibility profiling by ATAC-seq identified accessible regulatory regions that can be utilized to predict candidate enhancers related to metabolic disorders and hypothalamic development. In depth molecular, cellular, and functional experiments unveiled the responsiveness of the hPSC-derived hypothalamic neurons to hormonal stimuli, such as insulin, neuropeptides including kisspeptin, and incretin mimetic drugs such as Exendin-4, highlighting their potential utility as physiologically relevant cellular models for disease studies. In addition, differential glucose and insulin treatments uncovered adaptability within the generated ARC neurons in the dynamic regulation of POMC and insulin receptors. In summary, the establishment of this model represents a novel, chemically defined, and scalable platform for manufacturing large numbers of hypothalamic arcuate neurons and serves as a valuable resource for modeling metabolic and reproductive disorders.

Since the mid-twentieth century, obesity and its related comorbidities, notably insulin resistance (IR) and type 2 diabetes (T2D), have surged. Nevertheless, their underlying mechanisms remain elusive. Evolutionary medicine (EM) sheds light on these issues by examining how evolutionary processes shape traits and diseases, offering insights for medical practice. This review summarizes the pathogenesis and genetics of obesity-related IR and T2D. Subsequently, delving into their evolutionary connections. Addressing limitations and proposing future research directions aims to enhance our understanding of these conditions, paving the way for improved treatments and prevention strategies.

Several evolutionary hypotheses have been proposed to unmask the origin of obesity-related IR and T2D, e.g., the "thrifty genotype" hypothesis suggests that certain "thrifty genes" that helped hunter-gatherer populations efficiently store energy as fat during feast-famine cycles are now maladaptive in our modern obesogenic environment. The "drifty genotype" theory suggests that if thrifty genes were advantageous, they would have spread widely, but proposes genetic drift instead. The "behavioral switch" and "carnivore connection" hypotheses propose insulin resistance as an adaptation for a brain-dependent, low-carbohydrate lifestyle. The thrifty phenotype theory suggests various metabolic outcomes shaped by genes and environment during development. However, the majority of these hypotheses lack experimental validation. Understanding why ancestral advantages now predispose us to diseases may aid in drug development and prevention of disease. EM helps us to understand the evolutionary relation between obesity-related IR and T2D. But still gaps and contradictions persist. Further interdisciplinary research is required to elucidate complete mechanisms.

Genetic epidemiological studies have shown that numerous genetic variants cumulatively increase obesity risk. Although genetically predisposed individuals are more prone to developing obesity, it has been shown that physical activity can modify the genetic predisposition to obesity. Therefore, genetic data obtained from earlier studies, including 30 polymorphisms located in 18 genes, were analyzed using novel methods such as the total genetic score and Biofilter 2.4 software to combine genotypic and phenotypic information for nine obesity-related traits measured before and after the realization of the 12-week training program. The results revealed six genes whose genotypes were most important for post-training changes-LEP, LEPR, ADIPOQ, ADRA2A, ADRB3, and DRD2. Five noteworthy pairwise interactions, LEP × LEPR, ADRB2 × ADRB3, ADRA2A × ADRB3, ADRA2A × ADRB2, ADRA2A × DRD2, and three specific interactions demonstrating significant associations with key parameters crucial for health, total cholesterol (TC), high-density lipoprotein (HDL), and fat-free mass (FFM), were also identified. The molecular basis of training adaptation described in this study would have an enormous impact on the individualization of training programs, which, designed according to a given person's genetic profile, will be effective and safe intervention strategies for preventing obesity and improving health.

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

Metabolic and bariatric surgery (MBS) effectively treats obesity and related comorbidities, though individual responses vary. This systematic review examines how genetic variants influence MBS outcomes in morbidly obese patients. A comprehensive search in PubMed, Embase, Medline, and the Cochrane Library identified 1572 studies, with 52 meeting the inclusion criteria. Two reviewers independently filtered and selected studies, including relevant cross-references. Research focused on polymorphisms in genes such as UCP2, UCP3, 5-HT2C, MC4R, FKBP5, FTO, CAT haplotypes, LYPAL-1, PTEN, FABP-2, CNR1, LEP656, LEP223, GLP-1R, APOA-1, APOE, ADIPOQ, IL-6, PGC1a, TM6SF2, MBOAT7, PNPLA3, TCF7L2, ESR1, GHSR, GHRL, CD40L, DIO2, ACSL5, CG, TAS2R38, CD36, OBPIIa, NPY, BDNF, CLOCK, and CAMKK2. Most studies explored associations with post-surgery weight loss, while some examined metabolic, cardiovascular, taste, and eating behavior effects as well. Understanding the role of genetic factors in weight loss and metabolic outcomes post-MBS can help tailor personalized treatment plans for improved efficacy and long-term success. Further research with larger sample sizes and extended follow-up is needed to clarify the effects of many genetic variants on MBS outcomes in morbidly obese patients.

Excessive weight (overweight and obesity) is a common disorder involving genetic and environmental factors, associated with cardiovascular diseases, type-2 diabetes, and others. NOTCH1 is critical for the maintenance of stem cells and adult tissues, being reported as a key player in metabolism and adipogenesis in animals. Thus, we test the hypothesis that NOTCH1 Single Nucleotide Polymorphisms (SNPs) are associated with excessive weight. Participants from the census-based cohort SABE (Saúde, Bem Estar e Envelhecimento-Health, Well-Being, and Aging), carried out in the city of São Paulo-Brazil, were stratified into cases and controls according to BMI. We filter the SNPs located at the start and end positions of NOTCH1 and 50 Kb on both sides. We selected SNPs with minor allelic frequency (MAF) greater than or equal to 0.01 and Hardy-Weinberg equilibrium (p > 0.05) and r2 ≥ 0.8. We performed an association study with genotypes and haplotypes, as well as in silico functional analysis of the identified SNPs. We observed an association of the SNP rs9411207 with the risk of excessive weight, under log-additive model, and the genotype distribution showed an increased frequency of homozygous TT (OR 1.50, CI 1.20-1.88; p = 0.0002). The haplotype GAT constructed from this and other SNPs in high Linkage Disequilibrium was more frequent in excessive-weight individuals (p = 0.003). In silico analyses suggested that these SNPs are likely to affect the transcription of NOTCH1 and other genes involved in adipogenesis and metabolism. This is the first study reporting association between NOTCH1 SNPs and the risk of excessive weight. Considering the possibility of NOTCH1 modulation, additional population studies are important to replicate these data and confirm the usefulness of risk genotypes for management strategies of excessive weight.

The worldwide prevalence of individuals with an elevated body weight has increased steadily over the past five decades. Billions of research dollars have been invested to improve our understanding of the causes and consequences of having an elevated body weight. All this knowledge has, however, failed to influence populational body weight trajectories of most countries around the world. Research on the definition of "obesity" has also evolved. Body mass index (BMI), the most commonly used tool to make its diagnosis, has major limitations. In this review article, we will highlight evidence from observational studies, genetic association studies and randomized clinical trials that have shown the remarkable inter-individual differences in the way humans store energy as body fat. Increasing evidence also suggests that, as opposed to weight inclusive, lifestyle-based approaches, weight-centric approaches advising people to simply eat less and move more are not sustainable for most people for long-term weight loss and maintenance. It is time to recognize that this outdated approach may have produced more harm than good. On the basis of pathophysiological, genetic and clinical evidence presented in this review, we propose that it may be time to shift away from the traditional clinical approach, which is BMI-centric. Rather, emphasis should be placed on actionable lifestyle-related risk factors aiming at improving overall diet quality and increasing physical activity level in the general population.

Coffee beans have a long history of use as traditional medicine by various indigenous people. Recent focus has been given to the health benefits of coffee beans and its bioactive compounds. Research on the bioactivities, applications, and effects of processing methods on coffee beans' phytochemical composition and activities has been conducted extensively. The current review attempts to provide an update on the biological effects of coffee on type 2 diabetes (T2D) and its comorbidities.

Comprehensive literature search was carried out on peer-reviewed published data on biological activities of coffee on in vitro, in vivo and epidemiological research results published from January 2015 to December 2022, using online databases such as PubMed, Google Scholar and ScienceDirect for our searches.

The main findings were: firstly, coffee may contribute to the prevention of oxidative stress and T2D-related illnesses such as cardiovascular disease, retinopathy, obesity, and metabolic syndrome; secondly, consuming up to 400 mg/day (1-4 cups per day) of coffee is associated with lower risks of T2D; thirdly, caffeine consumed between 0.5 and 4 h before a meal may inhibit acute metabolic rate; and finally, both caffeinated and decaffeinated coffee are associated with reducing the risks of T2D.

Available evidence indicates that long-term consumption of coffee is associated with decreased risk of T2D and its complications as well as decreased body weight. This has been attributed to the consumption of coffee with the abundance of bioactive chemicals.

Susceptibility to metabolic syndrome (MetS) is dependent on genetics, environment, and gene-by-environment interactions, rendering the study of underlying mechanisms challenging. The majority of experiments in model organisms do not incorporate genetic variation and lack specific evaluation criteria for MetS. Here, we derived a continuous metric, the metabolic health score (MHS), based on standard clinical parameters and defined its molecular signatures in the liver and circulation. In human UK Biobank, the MHS associated with MetS status and was predictive of future disease incidence, even in individuals without MetS. Using quantitative trait locus analyses in mice, we found two MHS-associated genetic loci and replicated them in unrelated mouse populations. Through a prioritization scheme in mice and human genetic data, we identified TNKS and MCPH1 as candidates mediating differences in the MHS. Our findings provide insights into the molecular mechanisms sustaining metabolic health across species and uncover likely regulators. A record of this paper's transparent peer review process is included in the supplemental information.

The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality. Here, we developed an analytical framework, Cell-Stratified MR (csMR), to investigate cell-stratified causality through colocalizing GWAS signals with single-cell eQTL from different brain cells. By applying to obesity-related traits, our results demonstrate the cell-type-specific effects of GWAS variants on gene expression, and indicate the benefits of csMR to identify cell-type-specific causal effect that is often hidden from bulk analyses. We also found csMR valuable to reveal distinct causal pathways between different obesity indicators. These findings suggest the value of our approach to prioritize target cells for extending genetic causation studies.

Studies on the familial effects of body mass index (BMI) status have yielded a wide range of data on its heritability.

To assess the heritability of obesity by measuring the association between the BMIs of fathers, mothers, and their offspring at the same age.

This cohort study used data from population-wide mandatory medical screening before compulsory military service in Israel. The study included participants examined between January 1, 1986, and December 31, 2018, whose both parents had their BMI measurement taken at their own prerecruitment evaluation in the past. Data analysis was performed from May to December 2023.

Spearman correlation coefficients were calculated for offsprings' BMI and their mothers', fathers', and midparental BMI percentile (the mean of the mothers' and fathers' BMI cohort- and sex-specific BMI percentile) to estimate heritability. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% CIs of obesity compared with healthy BMI, according to parental BMI status.

A total of 447 883 offspring (235 105 male [52.5%]; mean [SD] age, 17.09 [0.34] years) with both parents enrolled and measured for BMI at 17 years of age were enrolled in the study, yielding a total study population of 1 343 649 individuals. Overall, the correlation between midparental BMI percentile at 17 years of age and the offspring's BMI at 17 years of age was moderate (ρ = 0.386). Among female offspring, maternal-offspring BMI correlation (ρ = 0.329) was somewhat higher than the paternal-offspring BMI correlation (ρ = 0.266). Among trios in which both parents had a healthy BMI, the prevalence of overweight or obesity in offspring was 15.4%; this proportion increased to 76.6% when both parents had obesity and decreased to 3.3% when both parents had severe underweight. Compared with healthy weight, maternal (OR, 4.96; 95% CI, 4.63-5.32), paternal (OR, 4.48; 95% CI, 4.26-4.72), and parental (OR, 6.44; 95% CI, 6.22-6.67) obesity (midparent BMI in the ≥95th percentile) at 17 years of age were associated with increased odds of obesity among offspring.

In this cohort study of military enrollees whose parents also underwent prerecruitment evaluations, the observed correlation between midparental and offspring BMI, coupled with a calculated narrow-sense heritability of 39%, suggested a substantive contribution of genetic factors to BMI variation at 17 years of age.

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.

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.

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).

Results of this study suggest for a sex-differentiated association between PCSK1 rs6235 and overweight/ obesity in Portuguese children.

Obesity's variability is significantly influenced by the interplay between genetic and environmental factors. We aimed to integrate the combined impact of genetic risk score (GRSBMI) with physical activity (PA), sugar-sweetened beverages (SSB), wine intake, and eating habits score (EHS) on obesity predisposition risk. Adults' (n = 5824) data were analyzed for common obesity-related single nucleotide polymorphisms and lifestyle habits. The weighted GRSBMI was constructed and categorized into quartiles (Qs), and the adjusted multivariate logistic regression models examined the association of GRSBMI with obesity (BMI ≥ 30) and lifestyle factors. GRSBMI was significantly associated with obesity risk. Each GRSBMI unit was associated with an increase of 3.06 BMI units (p ≤ 0.0001). PA markedly reduced obesity risk across GRSBMI Qs. Inactive participants' (≥90 min/week) mean BMI was higher in GRSBMI Q3-Q4 compared to Q1 (p = 0.003 and p < 0.001, respectively). Scoring EHS ≥ median, SSBs (≥1 cup/day), and non-wine drinking were associated with higher BMI within all GRSBMI Qs compared to EHS < median, non-SSBs, and non-wine drinkers. Mean BMI was higher in GRSBMI Q4 compared to other quartiles (p < 0.0001) in non-wine drinkers and compared to Q1 for SSB's consumers (p = 0.07). A higher GRSBMI augmented the impact of lifestyle factors on obesity. The interplay between GRSBMI and modifiable lifestyle factors provides a tailored personalized prevention and treatment for obesity management.