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Introduction: Obesity is a public health crisis in the USA. This study aimed to estimate the prevalence of obesity and severe obesity in US children and adolescents and identify novel targetable risk factors associated with childhood obesity. Methods: From the US National Health and Nutrition Examination Survey from 1999 to 2018, 35,907 children aged 2–19 with body mass index (BMI) data were included. Obesity and severe obesity were defined as BMI ≥95th percentile and ≥120% of 95th percentile of US Centers for Disease Control and Prevention growth charts, respectively. Trends in the prevalence of obesity and subgroup analyses according to socioeconomic factors and language used in the interview were analyzed. Results: The prevalence of obesity and severe obesity increased from 14.7 [95% confidence interval: 12.9–17.0]% to 19.2 [17.2–21.0]% and 3.9 [2.9–5.0]% to 6.1 [4.8–8.0]% in 1999–2018, respectively (p = 0.001 and p = 0.014, respectively). In 2017–2018, the prevalence of obesity among children from Spanish-speaking households was 24.4 [22.4–27.0]%, higher than children from English-speaking households (p = 0.027). Conclusion: The prevalence of childhood obesity kept increasing in 1999–2018. The problem is worse in children from Spanish-speaking households. Novel and targeted public health intervention strategies are urgently warranted to effectively halt the rising epidemic of childhood obesity.

Background: Growth differentiation factor 15 (GDF15) is a key regulator of body weight in animals by regulating food intake. Its receptor, glial cell-derived neurotrophic factor receptor alpha-like (GFRAL), was identified recently. Pre-clinical studies showed that it is a promising therapeutic target for cardiometabolic diseases and anorexia/cachexia. Although many pharmaceutical companies are developing drugs targeting GFRAL, whether the findings from animal studies can be extrapolated to man is unknown. Mendelian randomization (MR) is useful in investigating the relationship between risk factors and disease outcomes. We aimed to use a two-sample MR approach to evaluate the clinical usefulness of targeting GDF15 for cardiometabolic diseases. Methods: Genetic instruments and summary statistics for MR analyses were obtained from a large genome-wide association study (GWAS) of GDF15 and cardiometabolic outcomes (n = 27,394 to 644,875), including body mass index, waist-hip ratio, waist circumference, whole-body lean mass, fat percentage, Type 2 Diabetes, fasting glucose, glycated haemoglobin, fasting insulin, LDL-cholesterol, HDL-cholesterol, total cholesterol, triglycerides, coronary artery disease, and estimated BMD (eBMD). Conventional inverse variance weighted (IVW) method was adopted to obtain the causal estimates of GDF-15 with different outcomes; weighted median and MR-egger were used for sensitivity analyses. Findings: There was null association between GDF15 levels and anthropometric outcomes. One SD increase in genetically-determined GDF15 was significantly associated with reduced HDL-C (beta: -0.048SD; SE: 0.014; P = .001) but the result was not significant in sensitivity analyses. A consistent significant causal association was observed between GDF15 and eBMD in IVW (beta: 0.026 SD; SE: 0.005; P