Association between endogenous sex hormones and adiposity in youth across a weight status spectrum.

BACKGROUND: While endogenous sex hormones (e.g., testosterone, estradiol) are important factors regulating adipose tissue distribution, studies evaluating such relationships in youth across a wide weight status spectrum are limited. METHODS: We performed a cross-sectional analysis of 8-21-year-old youth. Multiple linear regression models were used to evaluate associations between sex hormones and adiposity measures (android/gynoid ratio (A/G), total fat mass (FM), visceral adipose tissue (VAT), waist circumference (WC)) and total lean mass (LM), adjusting for pubertal stage and race/ethnicity, and stratified by sex and weight status. RESULTS: Among 342 youth, the mean age was 13.0 ± 2.8 years old (52.6% female; 38.9% normal weight [NW]; 27.8% overweight/obesity [OW/OB]; 33.3% severe obesity [SO]). Testosterone was positively associated with LM among males with NW (1462 g, 95% CI: 255-2668 g) and OW/OB (3792 g, 95% CI: 1244-6340 g), with A/G and WC among males with NW (0.01, 95% CI: 0-0.2 and 10 mm, 95% CI: 4-16 mm, respectively), and negatively associated with WC among males with SO (-43 mm, -81 to -5 mm). Estradiol was positively associated with A/G, FM, and WC among males with SO, and VAT in females with NW. CONCLUSION: Our findings showed that sex hormones were associated with adipose tissue deposition in youth across the weight spectrum. IMPACT STATEMENT: Sex hormones (e.g., testosterone, estradiol) are associated with various adiposity measures among male and female children and adolescents across a weight status spectrum. We evaluated associations between sex hormones and various adiposity measures among 8-21-year-olds across a weight status spectrum (normal weight, overweight/class 1 obesity, class 2-3 obesity). We found that estradiol was positively associated with total fat mass, android/gynoid ratio, and waist circumference in males with class 2-3 obesity, and testosterone was positively associated with lean mass in males with normal weight and overweight/class 1 obesity. Sex hormones may influence, or may be influenced by, adiposity in youth.

PFHpA alters lipid metabolism and increases the risk of metabolic dysfunction-associated steatotic liver disease in youth-a translational research framework.

To address the growing epidemic of liver disease, particularly in pediatric populations, it is crucial to identify modifiable risk factors for the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology and severity of MASLD remains largely unexplored in humans. This study aims to bridge the gap between human and in vitro studies to understand how exposure to perfluoroheptanoic acid (PFHpA), one of the emerging PFAS replacements which accumulates in high concentrations in the liver, contributes to MASLD risk and progression. First, we showed that PFHpA plasma concentrations were significantly associated with increased risk of MASLD in obese adolescents. Further, we examined the impact of PFHpA on hepatic metabolism using 3D human liver spheroids and single-cell transcriptomics to identify major hepatic pathways affected by PFHpA. Next, we integrated the in vivo and in vitro multi-omics datasets with a novel statistical approach which identified signatures of proteins and metabolites associated with MASLD development triggered by PFHpA exposure. In addition to characterizing the contribution of PFHpA to MASLD progression, our study provides a novel strategy to identify individuals at high risk of PFHpA-induced MASLD and develop early intervention strategies. Notably, our analysis revealed that the proteomic signature exhibited a stronger correlation between both PFHpA exposure and MASLD risk compared to the metabolomic signature. While establishing a clear connection between PFHpA exposure and MASLD progression in humans, our study delved into the molecular mechanisms through which PFHpA disrupts liver metabolism. Our in vitro findings revealed that PFHpA primarily impacts lipid metabolism, leading to a notable increase of lipid accumulation in human hepatocytes after PFHpA exposure. Among the pathways involved in lipid metabolism in hepatocytes, regulation of lipid metabolism by PPAR-a showed a remarkable activation. Moreover, the translational research framework we developed by integrating human and in vitro data provided us biomarkers to identify individuals at a high risk of MASLD due to PFHpA exposure. Our framework can inform policies on PFAS-induced liver disease and identify potential targets for prevention and treatment strategies.

Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans. OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children. METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 17.1 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs. RESULTS: Plasma PFAS concentrations were associated with alterations in 475 miRNAs in the Teen-LABs study and 5 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis. CONCLUSION: Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.

Financial Incentives and Treatment Outcomes in Adolescents With Severe Obesity: A Randomized Clinical Trial.

Importance: Adolescent severe obesity is usually not effectively treated with traditional lifestyle modification therapy. Meal replacement therapy (MRT) shows short-term efficacy for body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) reduction in adolescents, and financial incentives (FIs) may be an appropriate adjunct intervention to enhance long-term efficacy. Objective: To evaluate the effect of MRT plus FIs vs MRT alone on BMI, body fat, and cardiometabolic risk factors in adolescents with severe obesity. Design, Setting, and Participants: This was a randomized clinical trial of MRT plus FIs vs MRT alone at a large academic health center in the Midwest conducted from 2018 to 2022. Participants were adolescents (ages 13-17 y) with severe obesity (≥120% of the 95th BMI percentile based on sex and age or ≥35 BMI, whichever was lower) who were unaware of the FI component of the trial until they were randomized to MRT plus FIs or until the end of the trial. Study staff members collecting clinical measures were blinded to treatment condition. Data were analyzed from March 2022 to February 2024. Interventions: MRT included provision of preportioned, calorie-controlled meals (~1200 kcals/d). In the MRT plus FI group, incentives were provided based on reduction in body weight from baseline. Main Outcomes and Measures: The primary end point was mean BMI percentage change from randomization to 52 weeks. Secondary end points included total body fat and cardiometabolic risk factors: blood pressure, triglyceride to high-density lipoprotein ratio, heart rate variability, and arterial stiffness. Cost-effectiveness was additionally evaluated. Safety was assessed through monthly adverse event monitoring and frequent assessment of unhealthy weight-control behaviors. Results: Among 126 adolescents with severe obesity (73 female [57.9%]; mean [SD] age, 15.3 [1.2] years), 63 participants received MRT plus FIs and 63 participants received only MRT. At 52 weeks, the mean BMI reduction was greater by -5.9 percentage points (95% CI, -9.9 to -1.9 percentage points; P = .004) in the MRT plus FI compared with the MRT group. The MRT plus FI group had a greater reduction in mean total body fat mass by -4.8 kg (95% CI, -9.1 to -0.6 kg; P = .03) and was cost-effective (incremental cost-effectiveness ratio, $39 178 per quality-adjusted life year) compared with MRT alone. There were no significant differences in cardiometabolic risk factors or unhealthy weight-control behaviors between groups. Conclusions and Relevance: In this study, adding FIs to MRT resulted in greater reductions in BMI and total body fat in adolescents with severe obesity without increased unhealthy weight-control behaviors. FIs were cost-effective and possibly promoted adherence to health behaviors. Trial Registration: ClinicalTrials.gov Identifier: NCT03137433.

Changes in plasma concentrations of per- and Polyfluoroalkyl substances after bariatric surgery in adolescents from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study.

Exposure to per- and poly-fluoroalkyl substances (PFAS) is ubiquitous due to their persistence in the environment and in humans. Extreme weight loss has been shown to influence concentrations of circulating persistent organic pollutants (POPs). Using data from the multi-center perspective Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort, we investigated changes in plasma-PFAS in adolescents after bariatric surgery. Adolescents (Mean age = 17.1 years, SD = 1.5 years) undergoing bariatric surgery were enrolled in the Teen-LABS study. Plasma-PFAS were measured at the time of surgery and then 6-, 12-, and 36 months post-surgery. Linear mixed effect models were used to evaluate longitudinal changes in plasma-PFAS after the time of bariatric surgery. This study included 214 adolescents with severe obesity who had available longitudinal measures of plasma-PFAS and underwent bariatric surgery between 2007 and 2012. Underlying effects related to undergoing bariatric surgery were found to be associated with an initial increase or plateau in concentrations of circulating PFAS up to 6 months after surgery followed by a persistent decline in concentrations of 36 months (p < 0.001 for all plasma-PFAS). Bariatric surgery in adolescents was associated with a decline in circulating PFAS concentrations. Initially following bariatric surgery (0-6 months) concentrations were static followed by decline from 6 to 36 months following surgery. This may have large public health implications as PFAS are known to be associated with numerous metabolic related diseases and the significant reduction in circulating PFAS in individuals who have undergone bariatric surgery may be related to the improvement of such metabolic related diseases following bariatric surgery.

Exposure to 4,4'-DDE in visceral adipose tissue and weight loss in adolescents from the Teen-LABS cohort.

OBJECTIVE: Dichlorodiphenyldichloroethylene (DDE), an obesogen accumulating in adipose tissue, is released into circulation with weight loss, although its impact is underexplored among adolescents. We tested the association using an integrative translational approach of epidemiological analysis among adolescents with obesity and in vitro measures exploring the impact of DDE on adipogenesis via preadipocytes. METHODS: We included 63 participants from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort. We assessed 4,4'-DDE in visceral adipose tissue at surgery and BMI and waist circumference at surgery and 0.5, 1, 3, and 5 years after. We conducted longitudinal analysis to estimate the interaction on weight loss between DDE and time since surgery. In vitro analysis quantified adipogenic differentiation in commercial human preadipocytes exposed to 4,4'-DDE via fluorescent staining and imaging. RESULTS: A dose-response relationship was observed, with the low-exposure group having a greater reduction in BMI during the first year compared to higher-exposure groups and showing smaller regains compared to higher-exposure groups after the first year. In vitro analysis of preadipocytes treated with 4,4'-DDE during adipogenic differentiation for 12 days showed a concentration-dependent increase in lipid accumulation. CONCLUSIONS: DDE could contribute to weight trajectory among adolescents undergoing bariatric surgery, potentially mediated via promoted adipogenesis in preadipocytes.

Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children and adolescents. NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), wherein hepatocellular inflammation and/or fibrosis coexist with steatosis. Circulating microRNA (miRNA) levels have been suggested to be altered in NAFLD, but the extent to which miRNA are related to NAFLD features remains unknown. This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents. AIM: To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD. METHODS: This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study. Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD. Plasma samples were collected during surgery for miRNA profiling. A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform. We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age, sex, race, and other key covariates. Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD. RESULTS: We identified 16 upregulated plasma miRNAs, including miR-193a-5p and miR-193b-5p, and 22 downregulated plasma miRNAs, including miR-1282 and miR-6734-5p, in adolescents with NAFLD. Moreover, 52, 16, 15, and 9 plasma miRNAs were associated with NASH, fibrosis, ballooning degeneration, and lobular inflammation, respectively. Collectively, 16 miRNAs were associated with two or more histological features of NAFLD. Among those miRNAs, miR-411-5p was downregulated in NASH, ballooning, and fibrosis, while miR-122-5p, miR-1343-5p, miR-193a-5p, miR-193b-5p, and miR-7845-5p were consistently and positively associated with all histological features of NAFLD. Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression, while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B. CONCLUSION: Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity. Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.

Evaluating appetite/satiety hormones and eating behaviours as predictors of weight loss maintenance with GLP-1RA therapy in adolescents with severe obesity.

INTRODUCTION: Whilst glucagon-like peptide-1 receptor agonists (GLP1-RAs) are effective for treating adolescent obesity, weight loss maintenance (WLM; preventing weight regain) remains a challenge. Our goal was to investigate appetite/satiety hormones and eating behaviours that may predict WLM with exenatide (a GLP1-RA) versus placebo in adolescents with severe obesity. METHODS: Adolescents who had ≥5% body mass index (BMI) reduction with meal replacement therapy were randomized to 52 weeks of once-weekly exenatide extended release or placebo. In this secondary analysis, eating behaviours and appetite/satiety regulation hormones post-meal replacement therapy (pre-randomization to exenatide or placebo) were evaluated as possible predictors of WLM. Percent change in BMI from randomization to 52 weeks served as the primary measure of WLM. RESULTS: The analysis included 66 adolescents (mean age 16.0 years; 47% female). Lower leptin response to meal testing was associated with greater WLM in terms of BMI percent change in those receiving exenatide compared to placebo (p = 0.007) after adjusting for sex, age and BMI. There were no other significant predictors of WLM. CONCLUSIONS: Prior to exenatide, lower leptin response to meals was associated with improved WLM with exenatide compared to placebo. The mostly null findings of this study suggest that GLP1-RA treatment may produce similar WLM for adolescents with obesity regardless of age, BMI, sex and eating behaviours.

SMART use of medications for the treatment of adolescent severe obesity: A sequential multiple assignment randomized trial protocol.

BACKGROUND: Severe obesity is a complex, chronic disease affecting nearly 9% of adolescents in the U.S. Although the current mainstay of treatment is lifestyle therapy, pediatric clinical practice guidelines recommend the addition of adjunct anti-obesity medication (AOM), such as phentermine and topiramate. However, guidance regarding when adjunct AOM should be started and how AOM should be used is unclear. Furthermore, an inherent limitation of current treatment guidelines is their "one-size-fits-all" approach, which does not account for the heterogeneous nature of obesity and high degree of patient variability in response to all interventions. METHODS: This paper describes the study design and methods of a sequential multiple assignment randomized trial (SMART), "SMART Use of Medications for the Treatment of Adolescent Severe Obesity." The trial will examine 1) when to start AOM (specifically phentermine) in adolescents who are not responding to lifestyle therapy and 2) how to modify AOM when there is a sub-optimal response to the initial pharmacological intervention (specifically, for phentermine non-responders, is it better to add topiramate to phentermine or switch to topiramate monotherapy). Critically, participant characteristics that may differentially affect response to treatment will be assessed and evaluated as potential moderators of intervention efficacy. CONCLUSION: Data from this study will be used to inform the development of an adaptive intervention for the treatment of adolescent severe obesity that includes empirically-derived decision rules regarding when and how to use AOM. Future research will test this adaptive intervention against standard "one-size-fits-all" treatments.

Bone mineral density in young adults 5 to 11 years after adolescent metabolic and bariatric surgery for severe obesity compared to peers.

OBJECTIVE: Metabolic and bariatric surgery (MBS) is associated with decreased bone mineral density (BMD) in adults. The long-term impact of MBS during adolescence on BMD is unknown. We report bone health status 5 to 11 years after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) from the Teen-LABS study cohort. METHODS: Between 2016 and 2022, BMD was measured by dual energy x-ray absorptiometry (DXA) in 106 young adults who had undergone MBS as adolescents. Volumetric BMD by peripheral quantitative computed tomography was measured on a subset. Ninety-one controls who had not undergone MBS were recruited for comparison. RESULTS: In cases (RYGB: mean age 26.8 ± 1.9 years, mean BMI 42.1 ± 9.9 kg/m2, VSG: mean age 25.1 ± 2.1 years, mean BMI 37.1 ± 8.4 kg/m2), compared to controls (mean age 26.5 ± 2.7 years, mean BMI 40.2 ± 8.7 kg/m2) (age p < 0.001, BMI p = 0.02), adjusted mean DXA-BMD (g/cm2) of the RYGB (n = 58) and VSG (n = 48) groups were lower at the hip (-10.0% and -6.3%), femoral neck (-9.6% and -5.7%) and ultra-distal radius (-7.9% and -7.0%; all p < 0.001), respectively. DXA-BMD did not differ between RYGB and VSG groups. Trabecular volumetric BMD at the radius and tibia were lower in the RYGB (-30% and -26%) and VSG (-15% and -14%) groups compared to the control group (p < 0.001). Greater time since MBS was associated with lower BMD Z-scores at the hip (p = 0.05) and femoral neck (p = 0.045). Percent change in body mass index (BMI) from baseline or in the first year after MBS were not associated with bone measures at a median of 9.3 years post MBS. CONCLUSION: BMD, especially of the hip and femoral neck, was lower in young adults who underwent MBS during adolescence compared to matched peers who had not undergone MBS. BMD Z-scores of the femoral neck were inversely associated with time since MBS but were not associated with BMI change.