Do adolescents with extreme obesity differ according to previous treatment seeking behavior? The Youth with Extreme obesity Study (YES) cohort.

OBJECTIVES: Adolescent extreme obesity is associated with somatic and psychiatric comorbidity, low quality of life, and social dysfunction. Nevertheless, few adolescents seek obesity treatment, thus many may elope appropriate care. We examine whether previous treatment seeking relates to disease burden, and whether previously non-treatment seeking adolescents accept diagnostic and therapeutic offers. This information is important to inform intervention strategies. METHODS: The Youth with Extreme obesity Study (YES) is a prospective, multicenter cohort study. We developed a novel recruitment strategy to span medical and vocational ascertainment settings and directly compare previously treatment seeking and non-treatment seeking youth. Participants aged 14-24 years; BMI ≥ 30 kg/m2 were enrolled at four medical- and one job centers. We present comorbidity and psycho-social baseline data by sex, obesity WHO grade I-III, and treatment-seeking status, defined as self-reported previous participation in a weight-loss program. RESULTS: Of 431 participants, 47% were male; mean age 16.6 (standard deviation 2.3) years, BMI 39.2 (7.5) kg/m2. Somatic comorbidity increased with obesity grade, p < 0.05: hypertension (42, 55, 64%), dyslipidemia (28, 24, 37%,), dysglycemia (9, 19, 20%,), elevated transaminases (15, 26, 30%). Quality of life (EQ5 D) decreased (74, 71, 70). Rates of psychiatric disorders were stable: depression 11%, attention deficit disorder 6%, substance use disorder 2%, self-injurious behavior 5%, suicide attempt 3%. Only 63% (56, 64, 69%) reported previous treatment seeking. Acceptance of the diagnostic (89%) or therapeutic (28%) program, medical or psychosocial situation did not differ by treatment seeking status. Acceptance of the therapeutic program was generally low, but high at the job center (92%). CONCLUSION: Irrespective of previous treatment seeking, adolescent extreme obesity was associated with high comorbidity and psychosocial burden. Acceptance of the diagnostic program overall and the therapeutic program at the job center were high. This underscores the need of innovative, accessible programs beyond the currently offered care.

MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency.

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.

A Structured, Manual-Based Low-Level Intervention vs. Treatment as Usual Evaluated in a Randomized Controlled Trial for Adolescents with Extreme Obesity - the STEREO Trial.

BACKGROUND: To compare efficacy and safety of a manual-based low-level psychological intervention with treatment as usual (weight loss treatment). METHODS: A two-armed randomized controlled trial without blinding and computer-based stratified block randomization included adolescents and young adults (14.0-24.9 years) with a BMI ≥ 30 kg/m2 at five German university hospitals. Primary outcomes were adherence (participation rate ≥ 5/6 sessions) and quality of life (DISABKIDS-37) 6 months after randomization. Secondary outcomes included depression, self-esteem, and perceived stress scores. RESULTS: Of 397 screened adolescents, 119 (mean BMI 40.4 ± 7.0 kg/m2, 49.6% female) were randomized to the manual-based low-level intervention (n = 59) or treatment as usual (n = 60). We observed no group difference for adherence (absolute risk reduction 0.4%, 95% CI -14.7% to 15.5%; p = 1.0) or health-related quality of life (score difference 8.1, 95% CI -2.1 to 18.3; p = 0.11). Among all secondary outcomes, we detected explorative evidence for an effect on the DISABKIDS-37 'social exclusion' subscale (score difference 15.5; 95% CI 1.6-29.4; p = 0.03). 18/19 adverse events occurred in 26 participants, none were classified as serious. CONCLUSION: Adherence to a coping-oriented intervention was comparable to weight loss treatment, although it was weak in both interventions. Psychological interventions may help to overcome social isolation; further confirmation is required.

Strong effect of pubertal status on metabolic health in obese children: a longitudinal study.

CONTEXT: The concept of metabolic healthy obese (MHO) status has been proposed also for children. However, it is unclear whether this is a stable status in childhood. OBJECTIVE: The aim was to analyze the changes of MHO status over time. DESIGN AND SETTING: This is 1-year longitudinal analysis of our obesity cohort. PARTICIPANTS: All obese children of our outpatient obesity clinic with 1-year follow-up were included. INTERVENTIONS: Standard care intervention was used. MAIN OUTCOME MEASURES: We examined body mass index (BMI), waist circumference, pubertal stage, blood pressure, fasting lipids, glucose, and insulin resistance index homeostasis model assessment (HOMA). MHO status was defined by absence of cardiovascular risk factors. RESULTS: A total of 2017 obese children (mean age, 11.6 ± 2.8 y; 45% male; BMI, 28.5 ± 5.3 kg/m(2); BMI-z score, 2.4 ±0.5) were enrolled onto the study, and 49.3% of the children were MHO at baseline. After 1 year, the majority of the MHO remained MHO (68.0%). MHO children were significantly younger, more frequently prepubertal, and less overweight compared with metabolic unhealthy obese (MUO) children (all P < .05). In the longitudinal analyses, entering into puberty (OR, 1.9; 95% confidence interval, 1.3-2.8]; P = .004) doubled the risk for switching from MHO to MUO, whereas changing from mid to late puberty nearly tripled the likelihood for switching from MUO to MHO (OR 3.1 [2.1-4.5], P < .001) in multiple logistic regression analyses adjusted for age, sex, and changes of body mass index standard deviation score (BMI-SDS). CONCLUSIONS: MHO is a stable status in childhood obesity as long as pubertal status remains stable. Due to the strong association between puberty and MUO status, the concept of MHO is questionable, at least in pubertal children.

Carotid intima-media thickness in children treated with growth hormone.

BACKGROUND: There is an ongoing discussion whether high doses of growth hormone (GH) may lead to cardiovascular diseases. Therefore, we studied the relationships between GH treatment and carotid intima-media thickness (cIMT), which is predictive of the development of atherosclerosis. METHODS: We measured cIMT in 38 children with supraphysiological doses of GH (mean age 10.9 ± 2.2 years; 47% male; GH indication: small for gestational age, n = 31; Turner syndrome, n = 5; SHOX deficiency, n = 2) and in 38 age- and gender-matched healthy children without GH treatment. Furthermore, we examined cIMT in 61 children with physiological doses of GH (mean age 12.0 ± 3.1 years; 64% male; GH indication: GH deficiency) and in 61 age- and gender-matched healthy children without GH treatment. Moreover, we analyzed blood pressure, lipids, HbA1c, IGF-1, and IGFBP-3 in children treated with GH. RESULTS: The cIMT levels did not differ significantly between children with and without GH treatment either in high-dose GH treatment or in physiological GH doses. In backwards linear regression analyses, cIMT was significantly related to HbA1c, but not to age, gender, BMI, pubertal stage, indication of GH treatment, duration or doses of GH treatment, IGF-1, IGFBP-3, or to any cardiovascular risk factor. CONCLUSIONS: We found no evidence that GH treatment is associated with changes in cIMT.

Changes in the serum metabolite profile in obese children with weight loss.

PURPOSE: Childhood obesity is an increasing problem and is accompanied by metabolic disturbances. Recently, we have identified 14 serum metabolites by a metabolomics approach (FIA-MS/MS), which showed altered concentrations in obese children as compared to normal-weight children. Obese children demonstrated higher concentrations of two acylcarnitines and lower levels of three amino acids, six acyl-alkyl phosphatidylcholines, and three lysophosphatidylcholines. The aim of this study was to analyze whether these alterations normalize in weight loss. METHODS: We analyzed the changes of these 14 metabolites by the same metabolic kit as in our previous study in serum samples of 80 obese children with substantial weight loss (BMI-SDS reduction >0.5) and in 80 obese children with stable weight status all participating in a 1-year lifestyle intervention. RESULTS: In the children without weight change, no significant changes of metabolite concentrations could be observed. In children with substantial weight loss, glutamine, methionine, the lysophosphatidylcholines LPCaC18:1, LPCaC18:2, and LPCa20:4, as well as the acyl-alkyl phosphatidylcholine PCaeC36:2 increased significantly, while the acylcarnitines C12:1 and C16:1, proline, PCaeC34:1, PCaeC34:2, PCaeC34:3, PCaeC36:3, and PCaeC38:2 did not change significantly. CONCLUSIONS: The changes of glutamine, methionine, LPCaC18:1, LPCaC18:2, LPCa20:4, and PCaeC36:2 seem to be related to the changes of dieting or exercise habits in lifestyle intervention or to be a consequence of overweight since they normalized in weight loss. Further studies should substantiate our findings.

FTO gene: association to weight regain after lifestyle intervention in overweight children.

OBJECTIVE: Polymorphisms in intron 1 of the 'fat mass and obesity-associated' (FTO) gene are associated with weight status. We hypothesized that the risk allele at a polymorphism in intron 1 of FTO is associated with weight regain after end of lifestyle intervention. METHODS: We longitudinally analyzed the changes of weight status as BMI-SDS in 346 unrelated overweight children (mean age 10.6 ± 2.6 years, 45% male, mean BMI-SDS 2.39 ± 0.49) both at the end of a 1-year lifestyle intervention and 1 year after the end of this intervention. We genotyped the obesity risk SNP rs9939609 at FTO by ARMS-PCR. RESULTS: The children reduced their BMI-SDS (-0.29 ± 0.33; p < 0.001) during intervention and increased their BMI-SDS between the end of intervention and 1 year later (+0.10 ± 0.41; p < 0.001). The obesity risk allele at FTO SNP rs9939609 was not associated with BMI-SDS reduction during the lifestyle intervention (p = 0.622), but with weight regain 1 year after end of the intervention in multiple linear regression analyses adjusted for age, sex, pubertal stage, and baseline BMI-SDS (Bonferroni corrected p = 0.002). CONCLUSIONS: The obesity risk allele at a polymorphism in intron 1 of FTO was associated with weight regain 1 year after a 1-year lifestyle intervention.

Relationships between 24-hour urinary free cortisol concentrations and metabolic syndrome in obese children.

CONTEXT: Clinical features of Metabolic Syndrome (MetS) and Cushing's Syndrome are similar, suggesting a pathogenetic role of hypothalamus-pituitary-adrenal axis in MetS. OBJECTIVE: The aim of the study was to determine whether MetS diagnosis and specific clusters of MetS components (waist circumference, dyslipidemia, hypertension, and impaired glucose metabolism) are associated with serum cortisol (SC) or 24-h urinary free cortisol (UFC) levels. DESIGN AND SETTING: We conducted cross-sectional analyses of data from our obesity cohort. We studied 264 obese children (age, 11.0 ± 2.8 years; male, 48%; BMI, 28.2 ± 5.4 kg/m(2)). We examined UFC, SC, homeostasis model assessment (HOMA), and features of MetS (waist circumference, blood pressure, fasting lipids, and glucose). RESULTS: Slightly increased UFC concentrations were measured in 30.7% of the children. Obese children with MetS had significantly (P = .003) higher UFC levels compared with obese children without MetS. Girls demonstrated significantly higher UFC concentrations compared with boys independent of pubertal stage. UFC and SC levels were significantly related to features of MetS, but the associations were stronger for UFC. In multivariate analyses adjusted for age, sex, and body mass index, none of the features of MetS but HOMA index was correlated with UFC, whereas SC demonstrated no significant association to any parameter of MetS or HOMA. CONCLUSIONS: Our findings support the hypothesis that changes in the hypothalamus-pituitary-adrenal axis are related to MetS in obesity. UFC seems to be a suitable marker for this relationship. Norm values for UFC adapted to obese children may help to avoid unnecessary dexamethasone suppression tests.

Components of the metabolic syndrome are negative predictors of weight loss in obese children with lifestyle intervention.

BACKGROUND AND AIMS: Insulin resistance has been proposed to be associated with weight gain in obesity. Therefore, we analyzed the impact of insulin resistance and its associated cardiovascular risk factors (CRFs) summarized in the Metabolic Syndrome (MetS) on change of weight status in obese children. METHODS: We analyzed 484 obese children who had participated in a lifestyle intervention and 533 obese children without lifestyle intervention. The changes of BMI-SDS in the time period of 1-year were related to baseline fasting insulin resistance index HOMA, blood pressure, waist circumference, waist-to-height ratio, lipids, uric acid, and HbA1c. RESULTS: In contrast to obese children without lifestyle intervention, BMI-SDS decreased and the majority of CRFs improved significantly in obese children with lifestyle intervention. Age, BMI, waist circumference, waist-to-height ratio, blood pressure, uric acid, triglycerides, and HOMA were negatively significantly related to reduction of BMI-SDS in children with lifestyle intervention. In multiple linear regression analysis adjusted for gender, pubertal stage, and treatment center (R² = 0.26), waist circumference (r = -0.016 [confidence interval -0.019 up to -0.013], p < 0.001) was the strongest negative predictor of weight loss in children with lifestyle intervention. In children without lifestyle intervention, we did not find significant relationships between change of BMI-SDS and CRFs including insulin resistance in multiple regression analysis. CONCLUSIONS: Insulin resistance and components of the MetS were associated negatively with weight loss in lifestyle intervention. Waist circumference at baseline was the strongest negative predictor of weight loss suggesting that obese children with abdominal fat distribution need more intensive interventions. This study is registered at clinicaltrials.gov (NCT00435734).

Short stature before puberty: which children should be screened for SHOX deficiency?

OBJECTIVE: We studied the prevalence of deficiency in the short stature homeobox containing gene (SHOX) in prepubertal short-statured children and analyzed the clinical and radiological signs. METHODS: Screening for SHOX deficiency was performed in 449 prepubertal short-statured children (54% females, aged 4-10 years) by direct sequencing and multiplex ligation probe-dependent amplification. Children with SHOX deficiency were compared to 1:2 age- and gender-matched prepubertal children without SHOX deficiency with respect to left-hand radiographs and anthropometrics including different ratios to height and proposed scores. RESULTS: We identified 22 (4.9%) patients with SHOX deficiency (64% point mutations). Children with SHOX deficiency demonstrated a mesomelic shortening of extremities. Lower leg lengths but not forearm length was reduced in children <8 years with SHOX deficiency. 36% of all children and none of the children <8 years with SHOX deficiency demonstrated any typical radiologic sign. Increased sitting height-to-height ratio and decreased extremities-to-trunk ratio demonstrated the best positive and negative predictive values to identify SHOX deficiency. CONCLUSIONS: Screening for SHOX deficiency seems rational, especially in children with increased sitting height-to-height ratio or decreased extremities-to-trunk ratio. These criteria were also valid in young children.

No impact of obesity susceptibility loci on weight regain after a lifestyle intervention in overweight children.

OBJECTIVE: An obesity risk allele at the NEGR1 locus was shown to be associated with weight regain after a lifestyle intervention in obese adults. Independent confirmation and studies in children are lacking. Therefore, we analyzed the impact of this and 11 additional obesity susceptibility loci on weight regain after a lifestyle intervention in overweight children. DESIGN AND METHODS: We longitudinally analyzed the changes in weight status as body mass index standard deviation score (BMI-SDS) in 282 overweight children (10.6 ± 2.5 years, 47% male, BMI 27.1 ± 3.9 kg/m2) both at the end of a 1-year lifestyle intervention and at 1 year after the end of intervention. We genotyped obesity risk single nucleotide polymorphisms (SNPs) derived from genome-wide association studies in or in proximity to the following genes: NEGR1, TNKS, SDCCAG8, FTO, MC4R, TMEM18, PTER, MTCH2, SH2B1, MAF, NPC1, and KCTD15. RESULTS: The children reduced their BMI-SDS (-0.28 ± 0.35; p<0.001) during intervention and increased their BMI-SDS between the end of intervention and 1 year later (+0.05 ± 0.36; p=0.027). None of the SNPs including NEGR1 was related significantly to weight regain. CONCLUSIONS: We found no evidence for effects of any of the GWAS-based obesity marker alleles on weight regain in the course of 1 year after an intervention.

Steroid hormone profiles in prepubertal obese children before and after weight loss.

CONTEXT: Little information is available on the steroid hormone profiles in obese children and their changes after weight loss. OBJECTIVE: We compared liquid chromatography-tandem mass spectrometry of serum steroid hormone profiles between obese and normal-weight children and studied the differential effects of weight loss on these hormones. DESIGN: This study was a cross-sectional comparison between obese and normal-weight children and a longitudinal 1-year follow-up study during lifestyle intervention in obese children. SETTING: The setting of the study was primary care. PATIENTS: Forty obese prepubertal (mean age 8.5 ± 2.1 years, 48% female, mean body mass index 24.8 ± 3.5 kg/m(2)) and 40 normal-weight children matched for gender, age, and pubertal stage. INTERVENTION: The study consisted of an outpatient 1-year intervention program based on exercise, behavior, and nutrition therapy. MAIN OUTCOMES MEASURES: Progesterone, 17-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, aldosterone, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, T, dihydrotestosterone, insulin resistance index of the homeostasis model assessment, and blood pressure were measured. RESULTS: Prepubertal obese children showed significantly increased androgens (DHEAS, androstenedione, T), mineralocorticoid precursor corticosterone, and glucocorticoids (11-deoxycortisol, cortisol, cortisone) compared with normal-weight children. In contrast to 20 obese children without weight loss, the 20 obese children with substantial weight loss demonstrated a significant decrease of cortisol, cortisone, and corticosterone. Androstenedione and T decreased but DHEAS remained elevated. Changes of the homeostasis model assessment correlated significantly positively with changes of cortisol (r = 0.38) and cortisone (r = 0.43) in partial regression analyses adjusted to changes of weight status. CONCLUSIONS: In obese prepubertal children, the increased androgens, mineralocorticoid precursors, and glucocorticoids were responsive to weight loss in contrast to DHEAS, suggesting that DHEAS does not seem to be regulated by changes in body mass index.

TSH and free triiodothyronine concentrations are associated with weight loss in a lifestyle intervention and weight regain afterwards in obese children.

OBJECTIVE: The impact of thyroid hormones on weight loss in lifestyle interventions and on weight regain afterwards is unknown. Therefore, we studied the relationships between TSH, free triiodothyronine (fT3), free thyroxine (fT4), and weight status, as well as their changes during and after a lifestyle intervention in obese children. MATERIALS AND METHODS: We evaluated the weight status as BMI-SDS in 477 obese children (mean age 10.6±2.7 years, 46% male, mean BMI 28.1±4.5  kg/m²) participating in a 1-year lifestyle intervention in a 2-year longitudinal study. Changes in BMI-SDS at 1 and 2 years were correlated with TSH, fT3, and fT4 concentrations at baseline and their changes during the intervention. RESULTS: A decrease in BMI-SDS during the intervention period (-0.32±0.38; P<0.001) was significantly positively associated with baseline TSH and fT3 in multiple linear regression analyses adjusted for age, sex, pubertal stage, and baseline BMI-SDS. An increase in BMI-SDS after the end of the intervention (+0.05±0.36; P=0.011) was significantly related to the decreases in TSH and fT3 during the intervention in multiple linear regression analyses adjusted for change in BMI-SDS during the intervention. In contrast to children with weight maintenance, children with weight regain after the end of the intervention demonstrated a decrease in their TSH levels (-0.1±1.6 vs +0.2±1.6  mU/l; P=0.03) and fT3 (-0.2±1.1 vs +0.3±1.6  pg/ml; P<0.001) during the intervention. CONCLUSIONS: The decreases in TSH and fT3 concentrations during the lifestyle intervention were associated with weight regain after the intervention. Future studies should confirm that the decreases in TSH and fT3 levels associated with weight loss are related to the change in metabolism such as resting energy expenditure.

Treatment with gonadotropin-releasing hormone analogues: different impact on body weight in normal-weight and overweight children.

OBJECTIVE: We studied the effect of gonadotropin-releasing hormone analogues (GnRHa) on weight gain as a possible side effect. METHODS: We analyzed longitudinally changes in BMI-SDS in 92 children [median age 8.0 years (IQR 7.1-8.9), 88% females, mean BMI-SDS 0.69 ± 1.30] with idiopathic central precocious puberty or early puberty treated with GnRHa. Furthermore, 25 overweight children with GnRHa were compared to 25 overweight children without GnRHa matched by age, gender, degree of overweight, and pubertal stage. RESULTS: The matched overweight children without GnRHa demonstrated a significant increase in their BMI-SDS in the course of 1 year (+0.18 ± 0.22). Normal-weight children treated with GnRHa demonstrated a significant increase in BMI-SDS in the course of 1 year (+0.32 ± 0.66) in contrast to overweight children treated with GnRHa who showed a stable BMI-SDS (-0.02 ± 0.27). This significant difference in changes in BMI-SDS between normal-weight and overweight children treated with GnRHa was also observed at the end of GnRHa treatment and 6 months later (p < 0.001). CONCLUSIONS: Change in weight status differed between overweight and normal-weight children during GnRHa treatment. We found no increased risk for the side effect of weight gain in overweight children treated with GnRHa.