Risk Of Severe Obesity Research Articles

Acquired hypothalamic obesity: A clinical overview and update.

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.

Assessing the performance of European-derived cardiometabolic polygenic risk scores in South-Asians and their interplay with family history

Background & aimsWe aimed to assess the performance of European-derived polygenic risk scores (PRSs) for common metabolic diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D) in the South Asian (SAS) individuals in the UK Biobank. Additionally, we studied the interaction between PRS and family history (FH) in the same population.MethodsTo calculate the PRS, we used a previously published model derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. Each PRS was adjusted according to an individual’s genotype location in the principal components (PC) space to derive an ancestry adjusted PRS (aPRS). We calculated the percentiles based on aPRS and stratified individuals into three aPRS categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates. Further, we measured the combined role of aPRS and first-degree family history (FH) in the SAS population.ResultsThe risk of developing severe obesity for SAS individuals was almost twofold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 1.95 (95% CI = 1.71–2.23, P < 0.01). At the same time, the risk of severe obesity was lower in the low-aPRS group (OR = 0.60, CI = 0.53–0.67, P < 0.01). Results in the same direction were found in the EUR data, where the low-PRS group had an OR of 0.53 (95% CI = 0.51–0.56, P < 0.01) and the high-PRS group had an OR of 2.06 (95% CI = 2.00-2.12, P < 0.01). We observed similar results for CAD and T2D. Further, we show that SAS individuals with a familial history of CAD and T2D with high-aPRS are associated with a higher risk of these diseases, implying a greater genetic predisposition.ConclusionOur findings suggest that CAD, obesity, and T2D GWAS summary statistics generated predominantly from the EUR population can be potentially used to derive aPRS in SAS individuals for risk stratification. With future GWAS recruiting more SAS participants and tailoring the PRSs towards SAS ancestry, the predictive power of PRS is likely to improve further.

Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer.

Adult survivors of childhood cancer have high rates of obesity, which, in combination with the cardiotoxic effects of specific cancer therapies, places them at high risk for cardiovascular morbidity. Here we show the contribution of genetic risk scores (GRSs) to increase prediction of those survivors of childhood cancer who are at risk for severe obesity (body mass index ≥40 kg m-2) as an adult. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the GRS was found to be associated with 53-fold-higher odds of severe obesity. Addition of GRSs to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction (area under the curve increased from 0.68 to 0.75, resulting in the identification of 4.3-times more high-risk survivors), which was independently validated in 6,064 individuals from the Childhood Cancer Survivor Study. Genetic predictors improve identification of patients who could benefit from heightened surveillance and interventions to mitigate the risk of severe obesity and associated cardio-metabolic complications.

Integration of rare expression outlier-associated variants improves polygenic risk prediction

Polygenic risk scores (PRSs) quantify the contribution of multiple genetic loci to an individual's likelihood of a complex trait or disease. However, existing PRSs estimate this likelihood with common genetic variants, excluding the impact of rare variants. Here, we report on a method to identify rare variants associated with outlier gene expression and integrate their impact into PRS predictions for body mass index (BMI), obesity, and bariatric surgery. Between the top and bottom 10%, we observed a 20.8% increase in risk for obesity (p= 3×10-14), 62.3% increase in risk for severe obesity (p= 1×10-6), and median 5.29 years earlier onset for bariatric surgery (p=0.008), as a function of expression outlier-associated rare variant burden when controlling for common variant PRS. We show that these predictions were more significant than integrating the effects of rare protein-truncating variants (PTVs), observing a mean 19% increase in phenotypic variance explained with expression outlier-associated rare variants when compared with PTVs (p= 2×10-15). We replicated these findings by using data from the Million Veteran Program and demonstrated that PRSs across multiple traits and diseases can benefit from the inclusion of expression outlier-associated rare variants identified through population-scale transcriptome sequencing.

Development and Implementation of a Pilot Integrative Day Hospital Program for Youth with Severe Obesity and Mental Health Issues.

Background: Adolescents with severe obesity and comorbid mental health issues are the most resistant to traditional weight management approaches and have poor treatment outcomes. Our objective was to implement and evaluate a pilot day hospital treatment program for adolescents with severe obesity, or risk for severe obesity, and significant mental health comorbidities. Methods: This was a prospective cohort study of adolescents 12-18 years of age with severe obesity (BMI >99th percentile), or at risk for severe obesity, and comorbid mental health issues. The intervention, focused on healthy lifestyle and mental health support, was implemented within an existing psychiatric day hospital at a pediatric quaternary care hospital. Anthropometric and mental health measures were analyzed pre- and postintervention. Results: Thirty-two adolescents with a mean age of 14.9 years [standard deviation (SD) 1.6] participated in the pilot integrative day hospital program for a mean duration of 5.2 months (SD 2.3). Eleven participants had primary severe obesity and comorbid mental health conditions (obesity subgroup) and 21 participants had primary mental illness and were at risk for obesity (psychiatry subgroup). We did not observe a significant difference between BMI pre- and postprogram among adolescents in both subgroups. In other words, adolescents in both subgroups achieved weight maintenance. Fear in losing control of overeating and/or being seen by others when eating decreased significantly in the obesity subgroup [mean difference (MD) 0.99; 95% confidence interval (CI): 0.27 to 1.71]. There was a significant decrease in participant-reported depression symptom severity, both overall and within program subgroups. Quality-of-life scores of study participants improved significantly within the obesity subgroup (MD -12.31; 95% CI: -21.69 to -2.93), but not within the psychiatry subgroup (MD -6.35; 95% CI: -13.37 to 0.67). Conclusions and Implications: A day hospital model of care may result in weight maintenance, decreased eating concerns, and improved mental health in adolescents with severe obesity or risk for severe obesity, and significant mental health comorbidities.

Nationwide Trends in Body Mass Index, Underweight, Overweight and Obesity Among Korean with Disabilities from 2008 to 2017

Background: The maintenance of optimal body weight is a crucial component in health and quality of life. However, little is known about weight distribution and trends among people with disabilities. This study in South Korea examined the 10-year trends of weight and prevalence of underweight, overweight and obesity according to disability grade and types compared with those without disabilities. Methods: We linked national disability registration data with national cancer screening program data. Age-standardized prevalence of underweight and obesity were analyzed for each year during the period 2008 to 2017, according to the presence, type, and severity of disabilities. Risk of underweight, overweight, obesity, and severe obesity were examined by multinomial logistic regression after adjusting for socio-demographic and clinical variables as of 2017. Findings: People with disabilities (both male and female) had a higher risk of underweight compared to those without disability (OR 1·41, 95% CI 1·38-1·44, and OR 1·31, 95% CI 1·28-1·34, respectively), especially in those with severe disabilities (OR 2·00, 95% CI 1·94-2·06 in male, and OR 1·83, 95% CI 1·77-1·89 in female, respectively). The age-standardized prevalence of severe obesity (BMI ≥30·0 kg/m2 ) was also higher in people with disability, and the disparity relative to people without disability widened from 1·8% in 2008 to 3·7% in 2017. Women with disabilities are more likely to be obese than those without disabilities regardless of disability severity (OR 1·40, 95% CI 1·38-1·41). The risk of severe obesity was also more prominent in women with disabilities (OR 2·08, 95% CI 2·05-2·11). Interpretation: Physical, mental and developmental disabilities were significantly associated with higher prevalence of obesity as well as underweight. The intersection of female gender, severe disability, and mental/developmental disabilities was associated with risk of severe obesity. Simultaneous efforts are needed to enhance food security as well as weight control and exercise for people with disabilities. Funding Statement: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Ministry of Science and ICT (MSIT) (No. 2019R1A2C1087507 and 2021R1C1C2008683) and the Korean Ministry of Education (No. 2019R1D1A3A03103862). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study protocol was approved by the Institutional Review Board of Chungbuk National University (CBNU-201910- BMETC-946-01)

Genetic Variants in the Activation of the Brown-Like Adipocyte Pathway and the Risk for Severe Obesity

Background: Regular physical activity has an important role in energy expenditure and combats the development of obesity. During exercise, PPARGC1A is overexpressed, stimulating an increase of the expression of FNDC5. This protein is cleaved to release the hormone irisin, which activates a browning process in white adipose tissue through an increase in UCP1 expression. As a result, irisin leads to mitochondrial heat production and energy expenditure. Objectives:The aim of this study was to investigate whether genetic variants in genes related to browning are associated with severe obesity and obesity-related features. This case-control study comprised 210 individuals with severe obesity (median body mass index [BMI] 45.6 [range 40.5–52.2]) and 191 normal-weight subjects (BMI 22.8 [21.1–23.9]). Methods: Genomic DNA was extracted from peripheral blood and the genotypes of the PPARGC1A(rs8192678, rs3736265, rs2970847, and rs3755863) and UCP1 (rs6536991 and rs12502572) genes were obtained using Taqman® assay. For the FNDC5 gene, screening of exons 3–5 as well as their intron-exon boundaries was performed using automatic sequencing. Results: Our results demonstrated that PPARGC1Ars2970847 and UCP1rs12502572 are associated with severe obesity. Furthermore, these polymorphisms influence anthropometric traits, such as BMI, body weight, and body adiposity index. Our findings also showed a dose-effect relationship between PPARGC1A rs8192678 and fasting plasma glucose. Finally, 5 rare mutations were identified in FNDC5, and 1 of these is a novel missense mutation. Conclusion: This study shows that genetic variants in the activation of brown-like adipocyte pathway play an important role in the susceptibility to severe obesity.

Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood

Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment.

Analysis of the Impact of Common Polymorphisms of theFTOandMC4RGenes with the Risk of Severe Obesity in Saudi Arabian Population

Obesity has reached epidemic proportions worldwide resulting in a serious public health problem. In Saudi Arabia, 28.7% of the population is obese due largely to the adoption of western dietary patterns over the last decade. The fat-mass and obesity associated (FTO) and melanocortin-4 receptor (MC4R) genes are ubiquitously expressed in the brain and pancreatic islets, and are the main link between the central nervous system and energy homeostasis based on food intake and energy expenditure. Genetic variants in the FTO and MC4R genes have been strongly associated with an increased obesity risk. To identify novel mutations in the MC4R gene and to perform correlation analyses of the known variants rs9939609 and rs1421085 in the FTO gene and rs17782313 near the MC4R gene in an obese Saudi population. A total of 136 obese patients and 104 healthy controls from King Fahd Hospital, Al-Khobar, were genotyped for single-nucleotide polymorphisms within or near the FTO and MC4R genes using the TaqMan assay. Leptin levels were determined by enzyme-linked immunosorbent assay. Targeted sequencing of MC4R exon was done by Sanger sequencing method. The study included 58 obese males and 78 obese females with a mean age of 39.78 ± 12.77 years and a mean body mass index (BMI) of 42.65 ± 9.03 kg/m2. A significant increase in the levels of leptin and triglycerides was associated with an increase of BMI. Other factors such as lactate dehydrogenase, gamma-glutamyltransferase, and high-density lipoprotein were also significantly higher in the severely obese cohort. The FTO polymorphisms were associated with a significantly increased risk for obesity and in BMI-stratified cohort, rs9939609 (T/A: odds ratio [OR] = 1.73, p = 0.007) and rs1421085 (T/C: OR = 1.56, p = 0.03) showed even stronger association. Genotyping for the near MC4R polymorphism, rs17782313 revealed an association with moderately obese patients (T/C: OR = 1.73, p = 0.038). The studied FTO gene polymorphisms were found to be significantly associated with increased BMI and were highly significantly associated with severe obesity. These FTO gene polymorphisms combined with a high-fat diet appear to promote early-onset obesity in the Saudi population. FTO polymorphisms appear to be universally associated with the risk of obesity, and further investigation into this genetic locus may provide clues for potential therapeutic targets.

Association Study of Three Gene Polymorphisms Recently Identified by a Genome-Wide Association Study with Obesity-Related Phenotypes in Chinese Children

Objective: This study aimed to examine associations of three single-nucleotide polymorphisms (SNPs) with obesity-related phenotypes in Chinese children. These SNPs were identified by a recent genome-wide association (GWA) study among European children. Given that varied genetic backgrounds across different ethnicity may result in different association, it is necessary to study these associations in a different ethnic population. Methods: A total of 3,922 children, including 2,191 normal-weight, 873 overweight and 858 obese children, from three independent studies were included in the study. Logistic and linear regressions were performed, and meta-analyses were conducted to assess the associations between the SNPs and obesity-related phenotypes. Results: The pooled odds ratios of the A-allele of rs564343 in PACS1 for obesity and severe obesity were 1.180 (p = 0.03) and 1.312 (p = 0.004), respectively. We also found that rs564343 was nominally associated with BMI, BMI standard deviation score (BMI-SDS), waist circumference, and waist-to-height ratio (p < 0.05). Conclusions: We showed for the first time that the rs564343 in PACS1 was associated with risk of severe obesity in a non-European population. This SNP was also found to be associated with common obesity and various obesity-related phenotypes in Chinese children, which had not been reported in the original study. The results demonstrated the value of conducting genetic researches in populations with different ethnicity.

Gender-Specific Effect of -102G>A Polymorphism in Insulin Induced Gene 2 on Obesity in Chinese Children.

Background. Insulin induced gene 2 (INSIG2) encodes a protein that has a biological effect on regulation of adipocyte metabolism and body weight. This study aimed to investigate the association of INSIG2 gene -102G>A polymorphism with obesity related phenotypes in Chinese children and test gender-specific effects. Methods. The 2,030 independent individuals aged from 7 to 18 years, including 705 obese cases and 1,325 nonobese controls, were recruited from local schools. We measured the obesity-related phenotypes and detected the serum lipids. We genotype -102G>A polymorphism by using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results. In all individuals, we found that the GG/GA genotype of INSIG2 -102G>A polymorphism was associated with risk of severe obesity (OR = 1.62, 95% CI: 1.11–2.36, and P = 0.012) under the dominant model. The association with severe obesity existed only in boys (OR = 1.91, 95% CI: 1.15–3.17, P = 0.012). The GG/GA genotype of -102G>A polymorphism was also associated with higher waist circumference (β = 2.61 cm, P = 0.031) in boys. No similar association was found in girls. The polymorphism was not associated with other obesity-related phenotypes, neither in all individuals nor in gender-specific population. Conclusions. This study identified a gender-specific effect of INSIG2 -102G>A polymorphism on risk of severe obesity and waist circumference in Chinese boys.

Association of Adolescent Obesity With Risk of Severe Obesity in Adulthood

Association of Adolescent Obesity With Risk of Severe Obesity in Adulthood

Association of Adolescent Obesity With Risk of Severe Obesity in Adulthood

Although the prevalence of obesity has increased in recent years, individuals who are obese early in life have not been studied over time to determine whether they develop severe obesity in adulthood, thus limiting effective interventions to reduce severe obesity incidence and its potentially life-threatening associated conditions. To determine incidence and risk of severe obesity in adulthood by adolescent weight status. A cohort of 8834 individuals aged 12 to 21 years enrolled in 1996 in wave II of the US National Longitudinal Study of Adolescent Health, followed up into adulthood (ages 18-27 years during wave III [2001-2002] and ages 24-33 years during wave IV [2007-2009]). Height and weight were obtained via anthropometry and surveys administered in study participants' homes using standardized procedures. New cases of adult-onset severe obesity were calculated by sex, race/ethnicity, and adolescent weight status. Sex-stratified, discrete time hazard models estimated the net effect of adolescent obesity (aged <20 years; body mass index [BMI] ≥95th percentile of the sex-specific BMI-for-age growth chart or BMI ≥30.0) on risk of severe obesity incidence in adulthood (aged ≥20 years; BMI ≥40.0), adjusting for race/ethnicity and age and weighted for national representation. In 1996, 79 (1.0%; 95% confidence interval [CI], 0.7%-1.4%) adolescents were severely obese; 60 (70.5%; 95% CI, 57.2%-83.9%) remained severely obese in adulthood. By 2009, 703 (7.9%; 95% CI, 7.4%-8.5%) non-severely obese adolescents had become severely obese in adulthood, with the highest rates for non-Hispanic black women. Obese adolescents were significantly more likely to develop severe obesity in young adulthood than normal-weight or overweight adolescents (hazard ratio, 16.0; 95% CI, 12.4-20.5). In this cohort, obesity in adolescence was significantly associated with increased risk of incident severe obesity in adulthood, with variations by sex and race/ethnicity.

Biomarkers of Endocannabinoid System Activation in Severe Obesity

BackgroundObesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined with genotyping for mutations in fatty acid amide hydrolase (FAAH) would identify circulating biomarkers of ECS activation in severe obesity.Methodology/Principal FindingsPlasma samples were obtained from 96 severely obese subjects with body mass index (BMI) of ≥40 kg/m2, and 48 normal weight subjects with BMI of ≤26 kg/m2. Triple-quadrupole mass spectroscopy methods were used to measure plasma ECS analogs. Subjects were genotyped for human FAAH gene mutations. The principal analysis focused on the FAAH 385 C→A (P129T) mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1±1.4 pmol/ml) and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3±1.0 pmol/ml) with wild-type FAAH genotype (p = 0.04), and significance was maintained after controlling for BMI.Conclusions/SignificanceSignificantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.

Association of Adolescent Obesity With Risk of Severe Obesity in Adulthood

Association of Adolescent Obesity With Risk of Severe Obesity in Adulthood

Gene‐Nutrition and Gene‐Physical Activity Interactions in the Etiology of Obesity

Gene‐Nutrition and Gene‐Physical Activity Interactions in the Etiology of Obesity

The role of surgery in obesity management

Obesity is unique because of the multiplicity of severe complications and the obscure etiology of the disease. Surgical treatment of obesity is also unlike most other surgery. It is neither pathology-oriented nor symptomatic: since the etiology of obesity is not known, the surgery can not have curative intent. Anti-obesity surgery is not a technical exercise, though technique is important, but rather should be seen as a behavioral intervention, requiring extensive preoperative education and life-long follow-up.The risks of most anti-obesity surgery have been reduced to levels significantly below the risk of severe obesity itself. Reduction of comorbidity and improvement in quality-of-life justify this treatment modality which is much more effective than all non-surgical methods in maintaining medically significant weight loss. Recent developments of minimally invasive techniques, with higher margins of safety and less discomfort, should increase the role of surgery in secondary prevention through earlier intervention.