Severe Childhood Obesity Research Articles

Complications of excess weight seen in two tier 3 paediatric weight management services: an observational study.

Children and young people living with severe obesity experience a range of complications of excess weight (CEW); however the prevalence of complications is not well defined. We have evaluated baseline characteristics and CEW of patients from two UK tier 3 paediatric weight management services. All new patients aged 2-17 years seen from March 2022 to February 2023 were included. Baseline demographic data was collected, and patients screened for CEW. PedsQL-4.0 questionnaires were used to assess health-related quality of life (HRQL). 185 patients were included, median age 14.3 years (range 3.3-18.0), 50.8% were girls. Of the patients, 73.8% were white British, with a significant excess of patients living in the most deprived decile (41.4%). Median body mass index SD score was +3.55 (IQR 3.11-3.90) and median body fat was 49.3% (IQR 42.3%-55.1%). Autistic spectrum disorder, attention deficit hyperactivity disorder and learning difficulties were vastly over-represented.Dyslipidaemia was the most common (51.6%) complication, followed by hypertension (28.9%), metabolic dysfunction-associated steatotic liver disease (17.8%), obstructive sleep apnoea (9.0%) and idiopathic intracranial hypertension (4.3%). Mean glycated haemoglobin was 35.0 mmol/mol (IQR 33-38). 8.1% had type 2 diabetes mellitus. Many of these complications were detected through screening in CEW clinics.Both child-reported (mean 51.9/100) and parented-reported (47.8/100) HRQL scores were low. Mental health problems were common: 26.2% with anxiety and 7.7% with depression. This study demonstrates the significant and profound mental and organ-specific pathology resulting from severe obesity in childhood, highlighting the clinical necessity for CEW clinics. A rigorous approach to identify complications at an early stage is essential to improve long-term health outcomes.

Weight loss and health status 10 years after laparoscopic adjustable gastric band insertion in adolescents: a follow-up report from Teen-LABS

BackgroundMetabolic and bariatric surgery is a safe and effective treatment strategy for severe childhood obesity, affecting 10% of US adolescents. ObjectivesThis prospective observational study addresses knowledge gaps related to changes in weight, cardiometabolic risk, and weight-related quality of life (WRQOL) in adolescents 10 years after laparoscopic adjustable gastric band (LAGB) insertion. SettingFive Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) US centers. MethodsAnthropometric, micronutrient, cardiometabolic risk, and WRQOL data were collected on 274 adolescents undergoing metabolic and bariatric surgery, of which 14 participants underwent LAGB insertion (2008–2011). Descriptive analyses compared outcomes from baseline to 10 years. ResultsParticipants were mostly female (86%), White (71%), with a median age of 18.5 years and preoperative median BMI of 49. Baseline prevalence of type 2 diabetes, hypertension, and dyslipidemia were 1 of 14 (7%), 8 of 14 (57%), and 8 of 13 (62%), respectively, versus 10-year prevalence of 1 of 8 (13%), 4 of 10 (40%), and 3 of 9 (33%), respectively. Two participants underwent LAGB removal (years 2 and 3), whereas two converted from LAGB to Roux-en-Y gastric bypass (years 2 and 6). Following initial BMI reduction (−10%) at year 1, 10-year median BMI in the LAGB retention group was 51, representing a 9.2% increase versus baseline. Micronutrient abnormalities and WRQOL remained similar between baseline and 10 years. One participant (1 of 14) withdrew from the study at year 7. ConclusionsLong-term follow-up of this cohort reveals that LAGB had minimal impact on BMI, cardiometabolic risk factors, and WRQOL among adolescents. These results confirm the limited efficacy of LAGB in the pediatric population.

Factors beyond Body Mass Index Associated with Cardiometabolic Risk among Children with Severe Obesity.

Background: The increasing prevalence of severe obesity among children and adolescents poses a significant challenge for pediatricians and general practitioners. This study aimed to investigate the relationships between biochemical results, anthropometry, blood pressure measurements, and bioimpedance analysis (BIA)-derived parameters to identify potential cardiometabolic complications associated with severe obesity. Methods: This study included 347 children (162 boys, 185 girls) aged 0-19 years, meeting the criteria for severe obesity based on BMI thresholds for different age groups. The patients were recruited in four pediatric endocrinology centers in Poland (Zabrze, Cracow, Rzeszow, Szczecin). Each participant underwent anthropometric measurements, pubertal stage assessment, blood pressure measurement, biochemical and hormonal tests, and BIA. Results: BMI showed significant associations with fat mass percentage (FM%) and waist-to-height ratio (WHtR) but not waist-to-hip ratio (WHR). The relationship between BMI and FM% was stronger in girls and prepubertal children. The metabolic syndrome (MetS) Z-score showed a strong positive correlation with BMI in the pubertal children. A negative correlation between HDL and triglycerides was observed only in the boys. The prepubertal children exhibited more significant correlations, despite a smaller sample size and shorter duration of obesity. Conclusions: Considering multiple parameters beyond BMI alone provides a better understanding of cardiometabolic risks associated with severe obesity in children. MetS Z-score was not a reliable indicator of increased cardiometabolic risk in younger children. Early-onset severe obesity was associated with a higher risk of metabolic complications. Early intervention is crucial to mitigate metabolic complications in this population.

Socioeconomic inequalities in severe childhood obesity: findings from a tier-3 paediatric weight management service

Socioeconomic inequalities in severe childhood obesity: findings from a tier-3 paediatric weight management service

Use of medical technology and daily weight measurements in the management of severe childhood obesity

Use of medical technology and daily weight measurements in the management of severe childhood obesity

Challenges and pitfalls of youth-onset type 2 diabetes.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) are increasing. The rise in frequency and severity of childhood obesity, inclination to sedentary lifestyle, and epigenetic risks related to prenatal hyperglycemia exposure are important drivers of the youth-onset T2DM epidemic and might as well be responsible for the early onset of diabetes complications. Indeed, youth-onset T2DM has a more extreme metabolic phenotype than adult-onset T2DM, with greater insulin resistance and more rapid deterioration of beta cell function. Therefore, intermediate complications such as microalbuminuria develop in late childhood or early adulthood, while end-stage complications develop in mid-life. Due to the lack of efficacy and safety data, several drugs available for the treatment of adults with T2DM have not been approved in youth, reducing the pharmacological treatment options. In this mini review, we will try to address the present challenges and pitfalls related to youth-onset T2DM and summarize the available interventions to mitigate the risk of microvascular and macrovascular complications.

Prevalence of Adolescents Meeting Criteria for Metabolic and Bariatric Surgery.

The American Academy of Pediatrics endorses metabolic and bariatric surgery (MBS) as a safe and effective treatment of severe obesity in children with class 3 obesity or with class 2 obesity and qualifying comorbidities. The study objective was to determine eligibility and characteristics of adolescents who qualify for MBS based on American Academy of Pediatrics guidelines. This retrospective cohort study analyzed electronic health record data of 603 051 adolescents aged 13 to 17 years between January 1, 2018, and December 31, 2021. Centers for Disease Control and Prevention criteria were used to define obesity classes 2 and 3. Multivariable logistic regression was used to evaluate the factors associated with meeting MBS eligibility criteria. Of the 603 041 adolescents evaluated, 22.2% had obesity (12.9% class 1, 5.4% class 2, and 3.9% class 3). The most frequently diagnosed comorbid conditions were gastroesophageal reflux disease (3.2%), hypertension (0.5%), and nonalcoholic fatty liver disease (0.5%). Among adolescents with class 2 obesity, 9.1% had 1 or more comorbidities qualifying for MBS, and 4.4% of all adolescents met the eligibility criteria for MBS. In multivariable modeling, males, Black and Hispanic adolescents, and those living in more deprived neighborhoods were more likely to meet MBS eligibility criteria. Overall, 1 in 23 adolescents met the eligibility criteria for MBS. Demographic and social determinants were associated with a higher risk for meeting these criteria. The study suggests that the health care system may face challenges in accommodating the demand for MBS among eligible adolescents.

O-16 Never too late: Delayed diagnosis of Prader-Willi syndrome

Abstract Introduction Prader-Willi syndrome (PWS) is the leading inherited cause of severe childhood obesity. The aim of this case report is to describe a case of delayed diagnosis of PWS and to emphasize the importance of early diagnosis of PWS. Clinical Case A 24-year-old young woman with a history of hyperphagia, severe obesity, and cognitive impairment was admitted to our department for glycemic control due to newly diagnosed type 2 diabetes mellitus. She also had obstructive sleep apnea, daytime sleepiness, scoliosis, short stature (148 cm), and impaired speech articulation. Central obesity (BMI:54.7 kg/m2, waist circumference 147 cm), cognitive impairment, and characteristic body and facial features (narrow bifrontal diameter, almond-shaped palpebral fissures, small hands and feet, strabismus) suggested a genetic disorder. Test results showed growth hormone 0.07 ng/mL (0-3.5) and IGF-1 46 ng/mL (191-478). Cytogenetic analysis was performed on GTG-banded metaphases obtained from peripheral blood lymphocyte culture. t(3;16)(p21;p13) was observed in the patient. Cytogenetic analysis of the parents showed that this translocation was of paternal origin. The SNRPN gene was amplified from the patient's genomic DNA by PCR using methylation-specific primers after bisulfite modification. PCR products were visualized by agarose gel electrophoresis. The methylation pattern was found to be consistent with PWS. Hypocaloric diet (1400 Kcal/day) metformin 2 g/day, liraglutide (dose gradually increased to 2.4 mg/day), and dapagliflozin 10 mg/day were started. During hospitalization, glycemic regulation was achieved and 5.4 kilograms of weight loss occurred. Conclusion Obesity-related complications (e.g. sleep apnea, type 2 diabetes) and behavioral problems contribute significantly to morbidity and mortality in individuals with PWS. Prevention and treatment of morbid obesity and related conditions in individuals with PWS and management of maladaptive behaviors are key goals that require long-term follow-up and attention to managing the process. In these adults with compulsive eating behaviors who lack the ability to make informed decisions, it is very challenging to ensure compliance with treatments such as obesity treatment and the use of assistive devices for sleep apnea, which require the patient's consent and compliance. The complexity of this multisystemic disease increases with age, and we emphasize the need for early diagnosis to reduce the morbidity and mortality associated with PWS.Figure 1.Used with the patient's and family's consent.

The Impact of Physical Exercises on Child Obesity

In recent years, there has been a noticeable increase in the number of cases of paediatric obesity, regardless of sociodemographic classification. Furthermore, the severity of obesity in children and adolescents has increased despite these rising instances. In the twenty-first century, childhood obesity and overweight have become significant public health concerns. Overweight and obesity are global issues that mostly impact low- and middle-income nations, particularly in metropolitan areas. In contrast, childhood obesity and overweight have caused more fatalities globally than childhood underweight. This review will discuss why early intervention to engage in childhood obesity issues is very important. It has been suggested that the obese children are at risk and have a have a higher likelihood of premature death. Currently proposed strategies to deal with childhood obesity include adapting a proper and healthy diet, limiting sedentary behaviour, and increasing physical activity. The effects of physical activity on body fat, insulin sensitivity and resistance, and metabolic factors in obese children, as well as the type, intensity, and duration of exercise, will be key topics of discussion. This review will shed light on how aerobic exercise, resistance training, and compound exercise differ in their effects on the risk of cardio-vascular disease in childhood obesity.

The Right Advice, from the Right Person, in the Right Way: Non-Engaged Consumer Families’ Preferences for Lifestyle Intervention Design Relating to Severe Obesity in Childhood

Family-based lifestyle interventions for children/adolescents with severe levels of obesity are numerous, but evidence indicates programs fail to elicit short- or longer-term weight loss outcomes. Families with lived experience can provide valuable insight as we strive to improve outcomes from programs. Our aim was to explore elements that families desired in a program designed to treat severe levels of obesity in young people. We recruited a cross-sectional sample of 13 families (parents and young people) who had been referred but had not engaged with the state-wide Perth Children’s Hospital, Healthy Weight Service (Perth, Australia), between 2016 and 2018. Utilizing semi-structured interviews and reflexive qualitative thematic analysis, we identified two broad themes, (1) bridging the gap between what to do and how to do it, and (2) peers doing it with you. The first theme reflected parents’ and young people’s feelings that programs ought to teach specialist-designed practical strategies utilizing non-generic information tailored to address the needs of the family, in a collaboratively supportive way, and encourage young people to learn for themselves. The second theme reflected the importance of social connection facilitated by peer support, and intervention programs should be offered in a group format to foster inclusion. Families indicated a willingness to engage in tertiary intervention programs but desired support from specialized health professionals/programs to be tailored to their needs, sensitive to their experiences and challenges and provide useful practical strategies that support the knowledge-to-action process.

OR07-01 Aberrant Expression Of Agouti Signaling Protein (ASIP) As A Cause of Monogenic Severe Childhood Obesity

Abstract Disclosure: K. Landgraf: None. E.T. Kempf: None. R. Stein: None. M. Hanschkow: None. Y. Tseng: None. T. Schöneberg: None. E. Zeggini: None. M. Blüher: None. A. Körner: None. Here we identified and characterized a heterozygous tandem duplication at the ASIP (agouti-signaling protein) gene locus causing ubiquitous, ectopic ASIP expression in a female index patient with extreme childhood obesity.From an adipose tissue sample of the patient, we observed pronounced and sustained differentiation potential of stroma-vascular fraction (SVF) cells into adipocytes in the patient compared to normal control cells. We further found reduced mitochondrial maximum respiration, spare capacity, and proton leak in the patient’s SVF cells as proxies for reduced energy expenditure. By transcriptome screen, we identified overexpression of one single gene, ASIP. We found and functionally confirmed a chromosomal rearrangement at the ASIP locus, that places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase (ITCH) promoter. The patient's phenotype of early-onset obesity, overgrowth, red hair, and hyperinsulinemia is concordant with that of mutant, so called agouti mice ubiquitously expressing the homolog nonagouti. Physiologically, ASIP antagonises the melanocortin 1 receptor (MC1R) in the skin. Due to its homology to the hypothalamic regulator of eating behaviour agouti-related protein (AGRP), we hypothesize that ectopic ASIP similarly influences eating behaviour via repressing melanocyte-stimulating hormone-mediated activation of MC4R and that the mutation might therefore represent a novel monogenic cause for severe childhood obesity. We show that the tandem duplication results in the ectopic generation of ASIP in patient-derived native stroma-vascular fraction (SVF) cells, adipocytes and blood cells as well as in induced pluripotent stem cells (iPSCs) generated from SVF cells of the patient, thus indicating ubiquitous ectopic ASIP expression. This overexpression persisted after differentiation of iPSCs into the three germ layers, mesoderm, ectoderm and endoderm, and after differentiation into hypothalamic-like neurons. Furthermore, we observed that ASIP causes a reduction of MC4R activity in vitro supporting the hypothesis that the obesity phenotype of our patient is caused by ectopic ASIP acting at the MC4R in the hypothalamus. Since the type of mutation escapes standard genetic screening algorithms, we rescreened the Leipzig childhood obesity cohort of 1745 patients and identified four additional patients with the identical mutation, ectopic ASIP expression and a similar phenotype. Taken together, our data indicate that ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity and might be potentially treatable with melanocortin 4 receptor agonists. Presentation: Thursday, June 15, 2023

Longitudinal Patterns of Beverage Intake in Treatment-Seeking Children with Obesity in Eastern NC Using the Validated BEVQ-15.

Sugar-sweetened beverage (SSB) consumption remains a major target for interventions to treat severe obesity in children. Understanding how total energy consumption is divided among different types of beverages remains unclear. This study retrospectively examined how the consumption of beverage calories (kcal) from 100% fruit juice and SSBs, and body mass index, assessed as a percent of the 95th sex- and age-specific percentile (%of 95BMI), changed during the treatment of children with obesity aged 2-18 years. Treatment was provided by an integrative multi-disciplinary team, comprising a physician, a dietician/ nutritionist and a behavioralist employing motivational interviewing and a small change approach to promote improved sustainable health habits and induce a net negative energy balance. The sample included 155 patients, with 341 visits. The median age was 11 years, 60% were girls, and there was a median follow-up of 3.1 months. At baseline, the median %of 95BMI was 135 and the median kcal/day intake was 436 from juice and 263 from SSB. For each additional 100 kcal consumed/day from SSB and juice, the %of 95BMI increased by 1.4 percentage points. In the follow-up, each additional month was associated with 7 fewer kcal/day from SSB and juice combined, with a 0.5 percentage point increase in %of 95BMI. Children in this treatment program consumed fewer calories from SSB over time, although the %of 95BMI did not decrease. SSBs other than soda accounted for the majority of beverage kcal intake, therefore potentially providing a targeted direction for interventions.

Cutoff values of body mass index for severe obesity in Korean children and adolescents: the 99th percentile versus 120% of the 95th percentile.

Several definitions for severe obesity have been used, primarily the 99th percentile of the body mass index (BMI) and 120% of the 95th BMI percentile. This study aimed to establish a standardized definition for severe obesity in children and adolescents in Korea. The 99th BMI percentile line and 120% of the 95th BMI percentile line were constructed using 2017 Korean National Growth Charts. To compare these 2 cutoff points for severe obesity, we included 9,984 individuals (5,289 males and 4,695 females) aged 10-18 years with anthropometric data available from the Korean National Health and Nutrition Examination Survey 2007-2018. Although 120% of the 95th percentile of BMI is widely used as a definition of severe obesity, the 99th percentile is almost identical to 110% of the 95th percentile in Korea, according to the latest national BMI growth chart for children and adolescents. The prevalence rates of high blood pressure, high triglycerides, low high-density lipoprotein cholesterol, and high alanine aminotransferase in the participants whose BMI was ≥120% of the 95th percentile were higher than in those whose BMI was ≥99th percentile (P<0.001). A cutoff value for severe obesity of ≥120% of the 95th percentile is appropriate in children and adolescents in Korea. To provide follow-up care for severely obese children and adolescents, it is necessary to add a new line at 120% of the 95th percentile to the national BMI growth chart.

Genetic Contributors to Obesity

Genetic forms of obesity contribute to ∼7% of severe obesity in children and adolescents. The exact global prevalence of monogenic and syndromic forms of obesity is not well established, most likely due to missed or delayed diagnosis. The challenge in determining the prevalence can be attributed to the lack of consensus on identifying and evaluating symptoms of genetic defects in a timely manner and hence a vastly undertested patient population. Further large-scale and long-term studies are needed to advance the understanding of this unique phenotype of obesity and effective treatment options."

Biallelic Mutations in P4HTM Cause Syndromic Obesity.

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.

A rare and challenging case of ROHHAD (Rapid-onset Obesity with Hypoventilation, Hypothalamic Dysfunction, Autonomic Dysregulation) syndrome

Rapid-onset Obesity with Hypoventilation, Hypothalamic Dysfunction and Autonomic Dysregulation is a rare and complex pediatric syndrome with unknown etiology. The disease hallmark is sudden and severe obesity in early childhood, with a later onset of central hypoventilation, responsible for high mortality. We present the case of a 2.5-year-old boy with sudden weight gain starting after 12 months of age (18 kg in a year) and hypoventilation in the setting of acute nasopharyngitis, requiring Non-Invasive Ventilation (NIV) initiation. Additionally, he presented symptoms and signs of autonomic disturbance, neurodevelopmental delay and behavior disorders. High prolactin, leptin and insulin were also present. Despite periodic adjustment of settings and adherence to NIV and great efforts to control food intake, he remained morbidly obese and died during an infectious intercurrence at 6 years of age. This case illustrates the challenging diagnosis and treatment/management of this rare syndrome, which can have a variable and not always complete presentation and has no specific diagnostic test available. Identifying hypoventilation and NIV treatment is essential to decrease morbimortality. However, most patients do not live past ten years old.

Haemophilia B, severe childhood obesity and other extra-haematological features associated with similar 4Mb-deletions on Xq27: Clinical findings, molecular insights and literature update.

Haemophilia B (HB) is associated with pathogenic variants in F9. Hemizygous deletions encompassing the entire F9 and proximate genes may express extra-haematological clinical phenotypes. To analyse the genotype/phenotype correlations in two unrelated boys with severe early childhood obesity (SCO), global developmental delay (GDD) and similar bleeding phenotype associated with comparable Xq27 deletions spanning the entire F9 and proximate genes, and characterise the pathogenic events estimating the most likely mutational mechanism involved. Entire F9-deletions were detected in three hemizygous unrelated probands with HB: two cases, C#1/C#2, presented SCO and GDD and a control patient (Co), who only had severe bleeding symptoms. Dense SNP-array and case-specific STS walking scan allowed characterisation of the deletion breakpoints. Extensive use of bioinformatics, statistics and clinical databases allowed the investigation of genotype-phenotype associations. Patients C#1/C#2 and Co resulted in a complete F9 and additional gene deletions of variable extensions on Xq26.3-Xq27.2 (C#1/C#2/Co: 4.3Mb/3.9Mb/160Kb). C#1/C#2 common deleted gene SOX3 is directly associated with SCO, GDD and pituitary hypothyroidism (PH) whilst C#2 extra-deleted gene MAGEC2 indirectly relates to anal atresia (AA). Breakpoint analysis revealed the involvement of the mechanisms of Alu/Alu recombination for the first time in HB and non-homologous or alternative end-joining. Our results represent the first report of unrelated patients with HB, SCO and GDD. This study and the literature update expand the spectrum of clinical findings and molecular insights observed in patients with HB caused by complete F9 and nearby SOX3 and MAGEC2 gene deletions, which may configure a contiguous gene syndrome.

Role of the Beta and Gamma Isoforms of the Adapter Protein SH2B1 in Regulating Energy Balance.

Human variants of the adapter protein SH2B1 are associated with severe childhood obesity, hyperphagia, and insulin resistance-phenotypes mimicked by mice lacking Sh2b1. SH2B1β and γ isoforms are expressed ubiquitously, whereas SH2B1α and δ isoforms are expressed primarily in the brain. Restoring SH2B1β driven by the neuron-specific enolase promoter largely reverses the metabolic phenotype of Sh2b1-null mice, suggesting crucial roles for neuronal SH2B1β in energy balance control. Here we test this hypothesis by using CRISPR/Cas9 gene editing to delete the β and γ isoforms from the neurons of mice (SH2B1βγ neuron-specific knockout [NKO] mice) or throughout the body (SH2B1βγ knockout [KO] mice). While parameters of energy balance were normal in both male and female SH2B1βγ NKO mice, food intake, body weight, and adiposity were increased in male (but not female) SH2B1βγ KO mice. Analysis of long-read single-cell RNA seq data from wild-type mouse brain revealed that neurons express almost exclusively the α and δ isoforms, whereas neuroglial cells express almost exclusively the β and γ isoforms. Our work suggests that neuronal SH2B1β and γ are not primary regulators of energy balance. Rather, non-neuronal SH2B1β and γ in combination with neuronal SH2B1α and δ suffice for body weight maintenance. While SH2B1β/γ and SH2B1α/δ share some functionality, SH2B1β/γ appears to play a larger role in promoting leanness.

Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity

Here we report a heterozygous tandem duplication at the ASIP (agouti signaling protein) gene locus causing ubiquitous, ectopic ASIP expression in a female patient with extreme childhood obesity. The mutation places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase promoter, driving the generation of ASIP in patient-derived native and induced pluripotent stem cells for all germ layers and hypothalamic-like neurons. The patient’s phenotype of early-onset obesity, overgrowth, red hair and hyperinsulinemia is concordant with that of mutant mice ubiquitously expressing the homolog nonagouti. ASIP represses melanocyte-stimulating hormone-mediated activation as a melanocortin receptor antagonist, which might affect eating behavior, energy expenditure, adipocyte differentiation and pigmentation, as observed in the index patient. As the type of mutation escapes standard genetic screening algorithms, we rescreened the Leipzig Childhood Obesity cohort of 1,745 patients and identified four additional patients with the identical mutation, ectopic ASIP expression and a similar phenotype. Taken together, our data indicate that ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity.

Targeted dietary approaches for the management of obesity and severe obesity in children and adolescents: A systematic review and meta-analysis.

There is a need for a detailed understanding of effective dietary interventions for children with obesity. This systematic review examined the effectiveness of diets of varying energy content as a component of weight treatment in children and adolescents with obesity, severe obesity and obesity-related comorbidity. A systematic search of six databases, from 2000 to 2021, for intervention studies of targeted dietary treatment for obesity in children aged 2-18 years identified 125 studies. Dietary interventions were grouped according to diet type and energy target. Risk of bias was assessed using the Effective Public Healthcare Panacea Project assessment tool. Meta-analysis examined change in body mass index (BMI) at intervention end. A broad array of diet types were effective at reducing BMI in children with obesity. When dietary types were considered by energy target, a gradient effect was observed. Very-low energy diets were most effective with a - 4.40 kg/m2 (n=3; 95% CI -7.01 to -1.79). While dietary interventions with no specified energy target were ineffective, resulting in a BMI gain of +0.17 kg/m2 (n=22; 95% CI 0.05 to 0.40). Practical definitions of dietary energy target in the management of obesity and severe obesity are urgently required to ensure treatment seeking children have timely access to efficacious interventions.