The role of adipose tissue and subsequent liver tissue hypoxia in obesity and early stage metabolic dysfunction associated steatotic liver disease.

BACKGROUND: Obesity is linked to several health complication, including Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD). Adipose tissue hypoxia has been suggested as an important player in the pathophysiological mechanism leading to chronic inflammation in obesity, and in the progression of MASLD. The study aims to investigate the effect of progressive obesity on adipose and liver tissue hypoxia. METHODS: Male 8-week-old C57BL/6J mice were fed a high-fat high-fructose diet (HFHFD) or control diet (CD) for 4, 8, 12, 16 and 20 weeks. Serum ALT, AST and lipid levels were determined, and glucose and insulin tolerance testing was performed. Liver, gonadal and subcutaneous adipose tissue was assessed histologically. In vivo tissue pO2 measurements were performed in gonadal adipose tissue and liver under anesthesia. A PCR array for hypoxia responsive genes was performed in liver and adipose tissue. The main findings in the liver were validated in another diet-induced MASLD mice model, the choline-deficient L-amino acid defined high-fat diet (CDAHFD). RESULTS: HFHFD feeding induced a progressive obesity, dyslipidaemia, insulin resistance and MASLD. In vivo pO2 was decreased in gonadal adipose tissue after 8 weeks of HFHFD compared to CD, and decreased further until 20 weeks. Liver pO2 was only significantly decreased after 16 and 20 weeks of HFHFD. Gene expression and histology confirmed the presence of hypoxia in liver and adipose tissue. Hypoxia could not be confirmed in mice fed a CDAHFD. CONCLUSION: Diet-induced obesity in mice is associated with hypoxia in liver and adipose tissue. Adipose tissue hypoxia develops early in obesity, while liver hypoxia occurs later in the obesity development but still within the early stages of MASLD. Liver hypoxia could not be directly confirmed in a non-obese liver-only MASLD mice model, indicating that obesity-related processes such as adipose tissue hypoxia are important in the pathophysiology of obesity and MASLD.

The Predictive Value of Adipokines and Metabolic Risk Factors for Dropouts and Treatment Outcomes in Children With Obesity Treated in a Pediatric Rehabilitation Center.

Background: Inpatient pediatric obesity treatments are highly effective, although dropouts and weight regain threaten long-term results. Preliminary data indicate that leptin, adiponectin, and cardiometabolic comorbidities might predict treatment outcomes. Previous studies have mainly focused on the individual role of adipokines and comorbidities, which is counterintuitive, as these risk factors tend to cluster. This study aimed to predict the dropouts and treatment outcomes by pre-treatment patient characteristics extended with cardiometabolic comorbidities (individually and in total), leptin, and adiponectin. Methods: Children aged 8-18 years were assessed before, immediately after and 6 months after a 12-month inpatient obesity treatment. Anthropometric data were collected at each visit. Pre-treatment lipid profiles; glucose, insulin, leptin, and adiponectin levels; and blood pressure were measured. The treatment outcome was evaluated by the change in body mass index (BMI) standard deviation score (SDS) corrected for age and sex. Results: We recruited 144 children with a mean age of 14.3 ± 2.2 years and a mean BMI of 36.7 ± 6.2 kg/m2 corresponding to 2.7 ± 0.4 BMI SDS. The 57 patients who dropped out during treatment and the 44 patients who dropped out during aftercare had a higher pre-treatment BMI compared to the patients who completed the treatment (mean BMI, 38.3 ± 6.8 kg/m2 vs 35.7 ± 5.5 kg/m2) and those who completed aftercare (mean BMI, 34.6 ± 5.3 kg/m2 vs 37.7 ± 6.3 kg/m2) (all p<0.05). Additionally, aftercare attenders were younger than non-attenders (mean age, 13.4 ± 2.3 years vs 14.9 ± 2.0, p<0.05).Patients lost on average 1.0 ± 0.4 SDS during treatment and regained 0.4 ± 0.3 SDS post-treatment corresponding to regain of 43 ± 27% (calculated as the increase in BMI SDS post-treatment over the BMI SDS lost during treatment). A higher BMI and more comorbidities inversely predicted BMI SDS reduction in linear regression (all p<0.05).The absolute BMI SDS increase after returning home was predicted by pre-treatment leptin and systolic blood pressure, whereas the post-treatment BMI SDS regain was predicted by pre-treatment age, leptin, and adiponectin levels (all p<0.05) in multivariate linear regressions. Conclusion: Patients who need treatment the most are at increased risk for dropouts and weight regain, emphasizing the urgent need for interventions to reduce dropout and support inpatients after discharge. Furthermore, this study is the first to report that pre-treatment leptin and adiponectin levels predict post-treatment BMI SDS regain, requiring further research.

The influence of parental body composition and lifestyle on offspring growth trajectories.

BACKGROUND AND OBJECTIVES: Parental body composition, physical activity (PA) and sedentary time (ST) have been linked with offspring body weight and health. However, independent contributions of body composition, PA and ST of both parents on growth trajectories of their offspring, taking into account sex differences, has not been investigated. METHODS: A total of 114 mother-father-child triads were included for analyses. Parental weight, height, PA and ST were objectively measured at 12 weeks of gestation. Gestational weight gain (GWG) and birthweight and -length were obtained from medical records. Offspring weight and length were measured repeatedly until 1 year of age. Longitudinal linear mixed models, stratified by offspring sex, were used to analyse the association between parental characteristics and offspring growth. RESULTS: GWG (positive association), maternal moderate-to-vigorous PA (negative association) and paternal ST (positive association) were associated with weight trajectories in girls but not in boys. Parental characteristics were not associated with offspring length trajectories. CONCLUSIONS: This study highlights the contribution of parental lifestyle characteristics on weight trajectories of their daughters during the first year of life. The paternal impact stresses the need to further investigate health behaviours of expecting fathers in relation to offspring health. Family-based interventions are needed with a focus on increasing PA and limiting ST in both parents.

Endothelial function and its determinants in children born after maternal bariatric surgery.

BACKGROUND: Children born from mothers who underwent bariatric surgery were found to have an improved lipid profile and lower CRP levels compared to siblings born before surgery. We hypothesized that surgery before pregnancy might also influence endothelial function in the offspring. METHODS: Blood sample analysis, blood pressure (BP) measurement, and peripheral arterial tonometry (PAT) were performed in 142 children (median age 10.5 years), either born from mothers who underwent bariatric surgery (BS) before pregnancy (n = 36) from mothers with overweight/obesity (OW/OB) (n = 71) or from normal weight (NW) mothers (n = 35), allowing the determination of the Reactive Hyperemia Index (RHI) in 111 children. RESULTS: Children of the BS group had a higher diastolic blood pressure SDS and a lower RHI compared to the children of the OW/OB and NW group (1.32 versus 1.37 in OW/OB and 1.70 in NW; p = 0.004). After log transformation and correction for age, weight SDS, BMI SDS, body fat percentage, and diastolic BP SDS, RHI was comparable between the groups. CONCLUSIONS: Children of mothers who underwent bariatric surgery before pregnancy do not have a disturbed endothelial function before puberty, when their increased diastolic BP and degree of adiposity is taken into account. IMPACT: Children born after maternal bariatric surgery have a higher diastolic blood pressure without impaired endothelial function. To our knowledge, this is the first study that investigates the vascular function of children based on maternal characteristics during pregnancy. Adult offspring of mothers with obesity during pregnancy have an increased cardiovascular mortality. Since we cannot demonstrate a childhood-onset primary vascular dysfunction, this cardiovascular vulnerability might be more related to the hypertension and body adiposity. Thus, more emphasis should be made on the prevention of obesity and hypertension in the offspring at risk for development of obesity.

Feasibility and Tolerance of Fingertip Peripheral Arterial Tonometry Measurements in School-Aged Children.

Background: Assessment of the endothelial function of the microvasculature by peripheral arterial tonometry (PAT) has gained increasing popularity in pediatrics. Discomfort or experienced pain during fingertip PAT has only been studied in adolescents and adults. Methods: In 142 children (aged 4-11 years old), a fingertip PAT with a commercial device (EndoPAT 2000®) as well as a caliper and ultrasound examination of peripheral skinfolds were performed as part of a cross-sectional cohort study. In 110 children, Faces Pain Scale (FPS-R) data were collected after PAT and skinfold measurements by caliper and ultrasound. Results: In 111 out of the 142 PAT measurements (78.2%), a reactive hyperemia index (RHI) could be obtained. The most frequent error messages by the software was a "too noisy" and/or a "poor quality" signal. The success rate was higher in children aged older than 6 years (83.1 vs. 44.4%; p < 0.001). Median (range) FPS-R after PAT was 0 (range 0-6) but was significantly higher than the median pain experienced after caliper measurements of peripheral skinfolds (p < 0.001). No pain was experienced by 59 of the 110 children (54.1%). Conclusion: PAT testing is feasible in the great majority of school-aged children, and the procedure is well-tolerated.

Psychogenic polydipsia in a female adolescent without a psychiatric background: A case report.

Psychological stress is a risk factor for primary polydipsia in adolescents without psychiatric comorbidity. Taking a detailed family and social history can help to distinguish primary polydipsia from diabetes insipidus in adolescents with challenging presentations of polydipsia and polyuria.

The Role of Brain-Derived Neurotrophic Factor in Obstructive Sleep Apnea and Endothelial Function in a Pediatric Population With Obesity.

BACKGROUND: Childhood obesity has increased worldwide, becoming a significant public health concern. Brain-derived neurotrophic factor (BDNF) plays an important role in the central regulation of food intake and body weight, but little is known regarding its role in childhood obesity. Next to obesity, BDNF has been linked to obstructive sleep apnea (OSA) and endothelial dysfunction, two obesity-related comorbidities. The aim of this study is to investigate how BDNF, OSA and endothelial dysfunction interact in children with obesity and to determine the effect of weight loss on serum BDNF levels. METHODS: Children and adolescents with obesity aged 8-18 years who were enrolled in a multidisciplinary obesity treatment (MOT) in a tertiary hospital, were prospectively included. Several examinations were conducted during this MOT; at baseline, after 6 months and after 12 months, including the assessment of endothelial function, body composition measurements and a polysomnography. BDNF levels were measured on a serum sample by means of ELISA. RESULTS: A total of 103 patients with obesity was included, of which 20 had OSA (19.4%). BDNF levels were comparable in children with obesity and OSA and children with obesity but without OSA (26.75 vs. 27.87 ng/ml, p = 0.6). No correlations were found between BDNF and sleep-related variables or between BDNF and endothelial function parameters nor between BDNF and adiposity measures. To investigate if the interaction between OSA and endothelial dysfunction had an influence on BDNF levels, a general linear model was used. This model revealed that a diagnosis of OSA, as well as the interaction between OSA and maximal endothelial dilatation, contributed significantly (p = 0.03, p = 0.04, respectively) to BDNF levels. After 1 year of weight loss therapy, BDNF levels did not change (26.18 vs. 25.46 ng/ml, p = 0.7) in our population. CONCLUSION: BDNF concentrations were comparable in children with obesity, both with and without OSA, indicating that BDNF levels are not affected by OSA. However, we did find an interaction effect of OSA and endothelial function on BDNF levels.

Adiposity, psychomotor and behaviour outcomes of children born after maternal bariatric surgery.

BACKGROUND: Bariatric surgery before pregnancy can result in improved maternal fertility. However, long-term data on the consequences at childhood age are currently lacking. METHODS: EFFECTOR is a prospective cohort study of children (aged 4 to 11 years) born to mothers who underwent bariatric surgery (BS) before pregnancy (n = 36), controls with overweight/obesity (OW/OB) matched on pre-pregnancy BMI (n = 36) and normal weight controls (NL) (n = 35). We performed prospective collection of anthropometric data, data on psychomotor development, school functioning and behaviour (Strengths and Difficulties Questionnaire (SDQ), Child Behaviour Checklist (CBCL)). RESULTS: The children born after bariatric surgery (BS) presented with the highest body-weight SDS (0.70 vs 0.14 in OW/OB and -0.09 in NL; P = .006) and BMI SDS (0.47 vs -0.02 in OW/OB and -0.42 in NL; P = .01). A higher excess in body fat percentage and waist circumference SDS were found in the BS group (5.7 vs 1.4 in OW/OB and -0.1 in NL; P < .001 and 0.61 vs 0.16 in OW/OB and -0.15 in NL; P = .04). The SDQ questionnaires revealed a higher amount of overall problems in the BS offspring (11.1 vs 7.5 in OW/OB and 8.1 in NL; P = .03), with a higher externalizing score at the CBCL (52.0 vs 44.2 in OW/OB and 47.0 in NL; P = .03). CONCLUSION: Maternal bariatric surgery does not appear to protect the offspring for childhood overweight and obesity. Parents reported more behaviour problems in these children, especially externally of nature.

Eating Habits of Children Born after Maternal Bariatric Surgery.

Mothers who underwent bariatric surgery (BS) before pregnancy have worrisome eating habits, but little is known about the eating habits of their offspring. EFFECTOR is a cross-sectional, long-term follow-up study of 4-11-year-old children born from mothers that underwent bariatric surgery before pregnancy (n = 36), mothers with overweight/obesity (OW/OB) in a control group (n = 71), and mothers with a normal weight (NW) in a second control group (n = 35). Data on anthropometry and on eating habits obtained through a Food Frequency Questionnaire were collected prospectively. The children's body mass index (BMI) scores significantly correlated with maternal pre-pregnancy BMI. The prevalence of overweight and obesity was the highest in children of the BS group (38.9% vs. 15.5% for children of the OW/OB group and 5.7% for those of the NW group; p = 0.004). Meal-skipping behavior was comparable between the groups. There was no difference in fruit and vegetable consumption. The BS group consumed more low-calorie sweetened beverages compared to the NW group (p = 0.01) but less fruit juice compared to the NW and OW/OB groups (p = 0.01). Our results may indicate a sugar-avoiding behavior in children of the BS group, fitting dietary maternal habits in a strategy to prevent dumping syndrome. In conclusion, maternal pre-pregnancy bariatric surgery does not alter unhealthy eating behaviors and the risk of development of overweight during childhood in their children.

How to Maximize Children's Involvement in Non-therapeutic Research-Lessons Learnt From EFFECTOR.

Background: Children are vulnerable study subjects, especially in non-therapeutic research. Nowadays more attention is paid to the children's voice in both decision-making on participation and their experience of clinical research procedures. Methods: We share our experiences from a long-term, cross-sectional, non-therapeutic follow-up study in the offspring of mothers who participated in scientific research during their pregnancy. Results: During the data collection process, different strategies were developed to achieve a satisfactory participation rate with a focus on the involvement of the children. All study documents and measurements were assembled into a superhero framework. This theme is flexible and attracts children of a wide age-span. In order to inform the children before the study visit, a visually attractive assent was created as well as a superhero video. During the study visit, a sticker diploma was used with similar visuals from the assent. The toddlers received a superhero-cape. The children were involved in the decision-making process during the whole process. Discussion and conclusion: From our experience during the EFFECTOR data collection process, parents and their children can be motivated to participate in a long-term, non-therapeutic, follow-up study when child friendly and adequate communication is used. Framing in a superhero theme is simple and suitable for children of a wide age-span.

Is vitamin D deficiency in obese youth a risk factor for less weight loss during a weight loss program?

BACKGROUND: Vitamin D deficiency is common in obese adolescents and a risk factor for insulin resistance. We investigated if prevailing serum 25-OH vitamin D might predict the body fat loss in a group of obese adolescents undergoing a residential weight loss program. METHODS: In 92 (35 male) obese adolescents (aged 10.6-19 years) undergoing a residential weight loss program in Belgium, fasting serum 25-OH vitamin D (25-OH-D), insulin, glucose and lipid levels were measured and body composition was assessed by dual-energy X-ray absorptiometry (DXA). RESULTS: Baseline median (range) serum 25-OH-D level was 17.7 µg/L (3.8-41.8). In total, 55 adolescents had a serum 25-OH-D below 20 µg/L. In 31 adolescents with a low baseline 25-OH-D level, median increase in serum 25-OH-D was 2.4 µg/L (-4.2 to 7.2) after 10 months. This resulted in normal 25-OH-D levels in seven adolescents, whereas median BMI decreased with 1.0 SDS and body fat percentage diminished with 9.9%. Obese adolescents with or without a 25-OH-D level below or above 20 µg/L at baseline had similar changes in body weight, BMI SDS, body fat percentage and body fat mass at the end of the program. The change in serum 25-OH-D did not correlate with change in serum insulin, BMI SDS or body fat percentage and body fat mass. CONCLUSION: Vitamin D deficiency was present in 55 out of 92 obese adolescents at the start of the summer. Serum 25-OH-D concentration did not predict changes in body fat loss after a residential weight loss program.

Effect of bariatric surgery before pregnancy on the vascular function in the offspring: protocol of a cross-sectional follow-up study.

BACKGROUND: The offspring of obese pregnant women are at risk for adverse metabolic, inflammatory and cardiovascular programming. Comprehensive long-term data are lacking on the contribution of changes in maternal weight after bariatric surgery before pregnancy compared with lifestyle interventions during pregnancy on the cardiovascular programming of the offspring. METHODS: EFFECTOR is designed as a cross-sectional cohort follow-up study targeting the children of different groups of women who were previously studied during their pregnancy. Four subgroups of children are identified, based on maternal weight characteristics during pregnancy: normal weight women, obese women without any intervention and obese women who underwent a lifestyle intervention during or bariatric surgery before pregnancy. Data collection is performed as a single study visit at home. Data on the sociodemographic situation, food habits and psychomotor development are obtained through questionnaires. During the home visit, extensive anthropometric and vascular assessment is performed. Information on body composition is provided by assessment of body weight and height, bioelectrical impedance analysis, skinfold measurements and ultrasound. Endothelial function is measured by non-invasive peripheral arterial tonometry (EndoPAT 2000). Biomarkers performed in blood and urinalysis conclude the data collection process. TRIAL REGISTRATION NUMBER: NCT02992106 (Pre-results).

Stüve-Wiedemann syndrome: recurrent neonatal infections caused by impairment of JAK/STAT 3 pathway.

Stüve-Wiedemann syndrome (OMIM #601559) is a rare, autosomal recessive disorder characterized by skeletal dysplasia, consecutive infections, feeding difficulties and autonomic dysregulation. We present an Afro-Caribbean family with two siblings diagnosed with Stüve-Wiedemann syndrome. The underlying loss-of-function mutation in the leukemia inhibitory factor receptor gene is thought to impair proper functioning of the JAK/STAT 3 pathway. As this affects normal functioning of T-helper cells, these patients are prone to infections with uncommon pathogens as illustrated by this case.

In utero programming and early detection of cardiovascular disease in the offspring of mothers with obesity.

The offspring of women with obesity during their pregnancy are exposed to an altered intra-uterine environment. A subsequent influence on the cardiovascular development during fetal life is assumed. In the present thematic review, we report on the current knowledge about this early development of cardiovascular disease from fetal life until adolescence. Based on animal studies, different contributing mechanisms have been hypothesized that still need confirmation in human subjects. Insulin resistance, increased levels of leptin, chronic inflammatory state, perturbation of sympathetic tone and epigenetic modifications contribute to a suboptimal nutrient environment and changed hemodynamics. The ensuing aberrant cardiomyocyte development, impaired endothelial cell relaxation and atherogenic lipid profile put these children at risk for the development of endothelial cell dysfunction. Increasing possibilities for early detection of this preliminary stage of atherosclerotic disease offer new insights into future prevention and treatment strategies. Future research should focus on further unraveling the effect of moderate intense, aerobic exercise. Since it is used to treat the condition in children and adolescents with good results, it might be a contributor to tackling endothelial cell dysfunction at its cradle when applied in early pregnancy.