Background: Alström syndrome is characterized by multiorgan dysfunction and obesity associated with impaired primary cilia function that may disrupt melanocortin-4 receptor (MC4R) pathway signaling. ...We evaluated the impact of ≥6 months of the MC4R agonist setmelanotide in patients with Alström syndrome. Methods: Patients with Alström syndrome aged ≥6 years were enrolled in Phase 2 and 3 trials of setmelanotide (NCT03013543, NCT03746522). Changes in weight, hunger, and quality of life (QOL) were evaluated. Clinical benefit was defined as meaningful improvement (ie, ≥5% body weight and/or body mass index BMI reduction for adults or ≥0.2 decrease in BMI Z score and/or ≥5-percentage point decrease in the percentage of the 95th percentile for BMI for pediatric patients, ≥25% decrease in hunger score, and/or increase in IWQOL-Lite score of >7.7 or increase in PedsQL score of >4.4). Adverse events (AEs) were assessed. Results: Eight patients received >6 months of treatment (range, 9.7-18.2 months). No patients aged >18 years achieved >5% body weight loss/BMI reduction; however, 1 of 2 adults (50%) had >25% decrease in hunger score. Five of 6 (83.3%) and 3 of 6 patients (50%) aged <18 years achieved >0.2- and >0.3-point decrease in BMI Z score, respectively. Three of 4 patients (75%) aged >12 to <18 years achieved >25% hunger score decrease. Two of 8 patients (25%) had improved QOL. Overall, 7 of 8 patients (87.5%) had improvement in >1 measure. Tolerability of setmelanotide was consistent with that in other rare MC4R disease populations. The most common AE was skin hyperpigmentation (10 of 12 patients 83.3%). Three patients discontinued treatment because of AEs; 1 AE (facial edema) was related to setmelanotide. Conclusions: Most patients with Alström syndrome had positive response regarding clinical benefit of setmelanotide across weight, hunger, and QOL. Further research into the full extent of clinical benefit and specific characteristics of responders is needed.
Background: Limited data exist regarding the association of degree of intentional weight reduction and incident obesity-related complications. Methods: Optum's Market Clarity database (2007-2020) was ...used to identify individuals >18 years of age with overweight/obesity, defined by body mass index (BMI), who intentionally reduced and maintained their weight (surgery, procedure, medication, lifestyle) from their highest BMI (index date) 6 months prior to and including the intervention start (pre-index period) over 3 years (weight reduction period). Follow-up continued until the earliest of end of clinical activity, death, pregnancy, or 29FEB2020. Individuals were classified by the age change BMI during the weight reduction period: 0%-<5%, 5%-<10%, 10%-<15%, 15%-<20%, 20%-<30%, and >30%. Kaplan-Meier analysis was used to estimate time to first diagnosis of type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) in follow-up among individuals with no diagnosis during the pre-index or weight reduction periods. Results: Of 145,944 eligible individuals, the mean age was 50.3 (SD 13.4) years, 71% were female, 15% were African American, and mean index BMI was 39.2 (SD 9.3). The largest and smallest BMI change cohorts were 0%-<5% (38.2%) and >30% (6.7%), respectively. Three years after the weight reduction period (6 years post index), T2D and ASCVD incidence was estimated at 6.0% and 5.7%, respectively, though incidence differed by degree of BMI reduction, p<0.001 for both (T2D diagnosis: 0%-<5%: 7.3%, 5%-<10%: 6.7%, 10%-<15%: 5.1%, 15%-<20%: 4.0%, 20%-<30%: 3.3%, and >30%: 3.2%; ASCVD diagnosis: 0%-<5%: 5.9%, 5%-<10%: 6.3%, 10%-<15%: 6.2%, 15%-<20%: 5.5%, 20%-<30%: 4.6%, and >30%: 3.7%). Conclusions: T2D and ASCVD incidence at six years post index were inversely associated with the degree of intentional weight reduction. For T2D, incidence decreased monotonically. For ASCVD, the association was not linear.
Background: In the past 30 years, obesity prevalence has doubled among adults in the U.S. and disproportionately affected ancestral minorities. The prevalence of severe obesity in the U.S. in 2013 ...was nearly twice as high in women (9.9%) as men (5.5%) and highest in minority groups, particularly Hispanic/Latinos (H/L). Environmental and genetic contributions to severe obesity are widely acknowledged, yet few studies have estimated the heritability of adult severe obesity. Methods: We assembled the largest multi-ancestral genome-wide association study (GWAS) of severe obesity phenotypes in 120,676 participants (62% female; 65% WHITE, 15% Black, 14% H/L, 3% East Asian). We estimated the heritability of three traits: age and sex stratified defined severe obesity 95th percentile body mass index (BMI) vs. 5-50th percentile BMI controls; class 3 obesity (BMI>40) vs. BMI<25 controls; and class 4 obesity (BMI>50) vs. BMI<25 controls. Further, we calculated the genetic correlation (rg) between each trait with BMI. We conducted analyses for the whole sample, and stratified by sex and self-reported ancestry, via linkage disequilibrium score regression. Results: The SNP-based heritability for 95th percentile BMI, class 3 obesity, and class 4 obesity is 0.13 (SE=0.01), 0.27 (0.01), and 0.29 (0.02), respectively. All three traits displayed rgs above 0.90 with BMI. Men had a significantly higher heritability than women for class 4 sity (0.05) vs. 0.31 (0.02). Heritability also differed by self-reported ancestry, with values of 0.17 (0.01), 0.37 (0.02), 0.52 (0.04) in WHITE participants, 0.11 (0.02), 0.22 (0.04), 0.08 (0.05) in BLACK participants, and 0.13 (0.03), 0.27 (0.05), 0.11 (0.08) in H/L, for 95th percentile BMI, class 3 obesity, and class 4 obesity, respectively. Conclusions: Results suggest distinct patterns of heritability by sex and ancestry. Although only limited evidence exists for sex- and ancestral-specific BMI loci, our study supports sex- and ancestral-specific GWAS for severe obesity traits.
Background: Obesity is common among African American and Hispanic children. Body mass index (BMI) is a more frequently reported measure of obesity than others, such as waist-to-height ratio (WHtR), ...which focuses on central obesity. We used 4 anthropometric measures to assess obesity and to characterize its relationships with children's characteristics, including age, sex, country of birth, ethnicity, and physical activity among children attending NYC Head Start. Methods: We analyzed baseline data from the Endotoxin Obesity and Asthma longitudinal study, in which mothers answered a demographic questionnaire about their child. We obtained anthropometric measurements (weight, height, skinfold thickness (SFT), and waist circumference) from children and calculated BMI, triceps and subscapular zscores, and WHtR. Results: Of 380 children, mean age 48 months, 50% were female. 25% of Mexican origin, 18% Dominican, 19% African American, 15% Puerto Rican, and 23% Other. Overall, 44% were above the 85th percentile for BMI. 75% had WHtR greater than 0.5 (obesity). Mean triceps SFT was at the 49th percentile and mean subscapular SFT at the 52nd percentile for age and sex. Children did not differ on BMI or subscapular SFTs by ethnic background. Mexican children had greater triceps z-scores (p=0.03) and WHtR (p<0.001) than others. Age was positively associated with subscapular z-score (p=0.02) and negatively associated with WHtR (p<0.001). US-born children had higher BMI z-scores than others. Conclusions: Overall, the adiposity profiles of children in the sample were poor but consistent with national data. Few factors were associated with adiposity measures, but Mexican origin was a risk factor for obesity.
Background: Increases in population waist circumference (WC) are happening at a different speed than body mass index (BMI). Assessing recent trends in WC and BMI gives us a better glimpse of how fat ...distribution has varied in and across populations and allows a better prediction of obesity associated-diseases. We investigated the changes in WC relative to BMI in five countries and assessed whether any secular changes in mean WC occurred independently of BMI. Methods: We used adult data from 1997 to 2020 from the US, England, Chile, Mexico and Peru nationally representative surveys. Sex-specific country-stratified (for the US, also race-/ethnicity) regressions were used to estimate the annual change in mean WC relative to BMI level, adjusting for age and survey year. We also tested interactions between BMI and survey year. Results: We observed increases in predicted mean WC for a given BMI level across countries except for Peru and USA-Non-Hispanic Black and USA-Mexican American populations. Overall results showed that mean WC among females increased more than males. Among females, mean WC increased more over time only at higher levels of BMI. The largest annual increase in WC was found in USA-Non-Hispanic White females (0.27cm/year, 95% CI 0.18, 0.36) with the largest reduction observed for Peru females (-0.27cm/year, 95% CI -0.46, -0.07) at BMI 35kg/m2. In contrast, males showed a more stable annual change in WC independently of BMI. Only significant increases were observed for Mexico and England males with the higher annual mean change observed for Mexico males at a BMI of 35 kg/m2 (0.14cm/year, 95% CI 0.08, 0.20). The largest reduction in WC was observed for Peru males (-0.47cm/year, 95% CI -0.76, -0.17) at that same BMI level. Conclusions: Over the last two decades, we observed across countries that secular increases in mean WC have been larger in females than males. These changes have largely occurred independently of the level of BMI. These differences bring a significant increase in disparities in abdominal obesity-associated diseases.
Body image distortion and/or dissatisfaction may occur primarily due to body fat accumulation and/or distribution. The aim of this study was to evaluate the frequency of body image perception and ...(dis)satisfaction categories in adult men and women according to the adiposity classification. This is a cross-sectional study (n = 514; 33-79 years; 265 women) that is part of a prospective cohort (Pró-Saúde study). Adiposity measurements were determined by two methods: anthropometry, used to calculate the body mass index (BMI) and dual-energy X-ray absorptiometry (DXA), to estimate body fat percentage. Participants were grouped as "no excess adiposity" and "excess adiposity", considering BMI and body fat percentage (>30% for men, >40% for women). Perception and (dis)satisfaction with body image were evaluated using the Kakeshita scale, composed by 15 silhouettes, developed for the Brazilian population. Degree of distortion (perceived BMI - real BMI) and dissatisfaction (perceived BMI - desired BMI) were calculated. A high proportion of men (58.6%; 74.3%), and especially of women (82.6%; 86.8%), presented body size overestimation and dissatisfaction due to excess weight, respectively. A relevant fraction of the women (32.6%) and men (30.8%) who were dissatisfied due to excess weight did not present excess adiposity, especially if classified by DXA. Variability in degree of distortion was hardly explained by anthropometric and DXA variables in women (<5%) and men (~22%). Both anthropometric and DXA measurements accounted for ~30% and ~50% of the variability in degree of dissatisfaction among women and men, respectively. Our results suggest a high frequency of body image distortion in Brazilian adult individuals, as well as dissatisfaction with excess weight, especially among women with excess adiposity. The findings indicate that anthropometric measurements explain much of the variability in degree of body image dissatisfaction in men, with no apparent advantage of the use of more refined DXA measurements.
