This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin pairs with large intrapair BMI differences (within-pair ΔBMI ≥ 3 kg/m2 ). Together, 3227 like-sexed twin pairs (34% monozygotic) were examined at age ~30 years in 1975 and followed up in 1981, 1990, and 2011. An individual's observed BMI in 1975 was considered within (±2.0), below (<-2.0), or above (>+2.0) genetically predicted BMI, measured by a polygenic risk score of 996,919 single nucleotide polymorphisms. In monozygotic and dizygotic twin pairs with large intrapair BMI differences, the co-twin with a higher observed BMI in 1975 deviated above predicted BMI more frequently (~2/3) than the co-twin with a lower BMI deviated below prediction (~1/3). Individuals below, within, and above prediction in 1975 reached, respectively, normal weight, overweight, and obesity by 2011, with a mean BMI increase of 4.5 (95% CI: 4.3-4.8). Categorizing BMI as below, within, or above polygenic risk score-predicted BMI helps identifying individuals who have been resistant or susceptible to weight gain. This may provide new insights into determinants and consequences of obesity.

There is little evidence on the genetic associations between life-course adiposity (including birth weight, childhood BMI, and adulthood BMI) and severe liver disease (SLD; including cirrhosis and liver cancer). The current study aimed to examine and contrast these associations. Genetic variants were obtained from genome-wide association studies. Two-sample Mendelian randomization (MR) analyses were performed to assess the genetic associations of life-course adiposity with SLD and liver biomarkers. Cox regression was used to estimate adjusted hazard ratios for SLD associated with genetic risk scores of life-course adiposity and adulthood weight change in the China Kadoorie Biobank. In observational analyses, genetic predispositions to childhood adiposity and adulthood adiposity were each associated with SLD. There was a U-shaped association between adulthood weight change and risk of SLD. In meta-analyses of MR results, genetically predicted 1-standard deviation increase in birth weight was inversely associated with SLD at a marginal significance (odds ratio: 0.81 [95% CI: 0.65-1.00]), whereas genetically predicted 1-standard deviation higher childhood BMI and adulthood BMI were positively associated with SLD (odds ratio: 1.27 [95% CI: 1.05-1.55] and 1.79 [95% CI: 1.59-2.01], respectively). The results of liver biomarkers mirrored those of SLD. The current study provided genetic evidence on the associations between life-course adiposity and SLD.

Incretin receptor agonists are now standard of care in treating obesity. Their efficacy and tolerability might be further improved by combining them with compounds that offer orthogonal mechanisms of action. The cannabinoid type 1 receptor (CB1R) is a clinically validated therapeutic target in obesity, and several experimental CB1R inverse agonists have been shown to induce weight loss. This study characterizes a novel CB1R inverse agonist (CRB-913) with similar preclinical potency to rimonabant but markedly reduced brain penetration. CRB-913 was tested as monotherapy and in combination with tirzepatide, semaglutide, or liraglutide in the diet-induced obesity (DIO) mouse model for body weight reduction. CRB-913 demonstrated enhanced plasma exposure (3.8-fold larger area under the curvelast ) and reduced brain levels (9.5-fold lower area under the curvelast ) than rimonabant. CRB-913 monotherapy yielded a dose-dependent decrease in body weight in DIO mice reaching -22% within 18 days. In further DIO studies in combination with tirzepatide, semaglutide, or liraglutide, CRB-913 (2.5 mg/kg) resulted in -32.6%, -28.8%, and -16.8% decreases in body weight on Day 18, respectively, with concomitant improvements in body fat content, liver triglycerides, and liver fat deposits. CRB-913 in combination with incretin analogues could deliver meaningful improvements over current standards of care for obesity and related conditions.

The aim of this study was to investigate the mediating role of child brain structure in the relationship between prenatal gestational diabetes mellitus (GDM) exposure and child adiposity. This was a cross-sectional study of 9- to 10-year-old participants and siblings across the US. Data were obtained from the baseline assessment of the Adolescent Brain Cognitive Development (ABCD) Study®. Brain structure was evaluated by magnetic resonance imaging. GDM exposure was self-reported, and discordance for GDM exposure within biological siblings was identified. Mixed effects and mediation models were used to examine associations among prenatal GDM exposure, brain structure, and adiposity markers with sociodemographic covariates. The sample included 8521 children (7% GDM-exposed), among whom there were 28 sibling pairs discordant for GDM exposure. Across the entire study sample, prenatal exposure to GDM was associated with lower global and regional cortical gray matter volume (GMV) in the bilateral rostral middle frontal gyrus and superior temporal gyrus. GDM-exposed siblings also demonstrated lower global cortical GMV than unexposed siblings. Global cortical GMV partially mediated the associations between prenatal GDM exposure and child adiposity markers. The results identify brain markers of prenatal GDM exposure and suggest that low cortical GMV may explain increased obesity risk for offspring prenatally exposed to GDM.

Information about excess adiposity markers different from BMI and iron status is limited and more so about the shape of these associations. This study evaluated the relationship between three adiposity markers and iron-deficient status in reproductive-age women. Cross-sectional analysis in 6357 non-pregnant women from the Colombian nutritional health survey (ENSIN) 2010. Exposures were the following: waist circumference (WC), waist-to-height ratio (W-HtR), BMI, and WC > 80 cm, W-HtR > 0.5, and BMI ≥ 25 and ≥30. Outcomes were the following: iron deficiency (ID) as serum ferritin <15 μg/L, ID as ferritin <30 μg/L, anemia, and continuous values of ferritin and hemoglobin. Logistic and linear regressions adjusted for sociodemographic/inflammation covariates were conducted. All the adiposity markers, continuous or categorical, were inversely and significantly associated with both ID thresholds in fully adjusted models (p < 0.05). W-HtR reported stronger effect estimates for ID (odds ratios < 0.5) and for prediction of log-ferritin levels (fully adjusted β-coefficient [95% CI] 0.61 [0.39-0.82], p < 0.01) and was also inversely associated with anemia (p < 0.05). In cubic splines analyses, W-HtR, WC, and BMI were linearly associated with ID from values closer to international thresholds of general or central obesity, and the patterns of WC and BMI tended toward flatness. A significant decline in the likelihood of anemia was steeper by increasing W-HtR than by increasing BMI. After exclusion of women with C reactive protein > 5 mg/L or adjustment for C reactive protein, adiposity markers remained significantly related to ferritin levels and W-HtR with anemia. Women with higher adiposity were less likely to have an iron-deficient status. W-HtR was the strongest and most consistently associated marker. Inflammation would not be involved in the associations found.

Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10-8 , explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.

Binge-eating disorder (BED) is a prevalent psychiatric disorder associated with obesity. Few evidence-based treatments exist for BED, particularly pharmacological options. This study tested the efficacy of naltrexone/bupropion for BED. A randomized, double-blind, placebo-controlled, 12-week trial tested naltrexone/bupropion for BED with and without obesity. Eighty-nine patients (70.8% women, 69.7% White, mean age 45.7 y, mean BMI 35.1 kg/m2 , 77.5% with BMI ≥ 30 kg/m2 ) were randomized to placebo (n = 46) or naltrexone/bupropion (n = 43), with randomization stratified by obesity status and gender; 92.1% completed post-treatment assessments. Mixed models of binge-eating frequency revealed significant reductions that did not differ significantly between naltrexone/bupropion and placebo. Logistic regression of binge-eating remission rates revealed that naltrexone/bupropion and placebo did not differ significantly. Obesity status did not predict, or moderate, binge-eating outcomes considered either continuously or categorically. Mixed models revealed that naltrexone/bupropion was associated with significantly greater percentage weight loss than placebo. Logistic regression revealed that naltrexone/bupropion had significantly higher rates of attaining ≥5% weight loss than placebo (27.9% vs. 6.5%). Obesity status did not predict or moderate weight-loss outcomes. Naltrexone/bupropion did not demonstrate effectiveness for reducing binge eating relative to placebo but showed effectiveness for weight reduction in patients with BED. Obesity status did not predict or moderate medication outcomes.

The body mass index (BMI; weight/height2 ), providing no information about the relative size of any adipose tissue depots, may accordingly misclassify degrees of cardiometabolic risk. However, in supine persons the abdominal height above the exam table (the sagittal abdominal diameter, SAD) is associated preferentially with the accumulation of visceral fat. Since visceral fat is a marker of insulin resistance, type 2 diabetes, coronary heart disease, and hypertension, SAD could contribute to the estimation of generalized cardiometabolic risk. The SAD has been measured inexpensively by a sliding-beam caliper in small studies and in the US National Health and Nutrition Examination Survey (NHANES). Cross-sectional models found that the SAD/height ratio (SADHtR) is more strongly associated than the waist circumference/height ratio or BMI with intermediary predictors of cardiometabolic disease. Prospective studies are needed, however, to demonstrate how well SAD or SADHtR might predict major disease outcomes or all-cause mortality.