Twelve-Month Outcomes after Metabolic and Bariatric Surgery among Youths Participating in a Structured Preparation and Follow-Up Program: Results of the Youth with Extreme Obesity Study.

INTRODUCTION: While invasive and associated with risks, metabolic and bariatric surgery (MBS) can promote sustained weight loss and substantial health benefits in youths with extreme obesity. The path toward informed decision making for or against MBS is poorly characterized and postoperative follow-up to assess risks and benefits is inconsistent. In youths with extreme obesity, we aimed to evaluate decision making toward MBS, as well as MBS outcomes and adherence with follow-up and recommendations in the setting of a structured pre- and post-MBS program. METHODS: Participants were recruited in the setting of the multicenter "Youth with Extreme Obesity Study" (YES). YES is a cohort study in adolescents and young adults aged 14-24 years with obesity (BMI ≥30.0 kg/m2) who were recruited at four medical centers and one job center in Germany between 2012 and 2018. Participants at two medical centers with BMI ≥35 kg/m2, aged 14-24 years, and interested in pursuing MBS were included in the subproject 3 "Safety and effectiveness of weight loss surgery in adolescents with severe obesity within a structured pre- and post-surgery treatment program - an observational study" that comprised a 2-months pre- and 12-months post-MBS program. RESULTS: Twenty-eight of 169 youths (17%) with BMI ≥35 kg/m2 were interested in MBS. Twenty-six fulfilled published eligibility criteria for MBS and participated in the structured pre-MBS preparation program. Of these, 9 participants (2 females) decided against, and 17 (n = 11 females) decided for MBS (sleeve gastrectomy). The 12-month follow-up rate was high (16/17 [94%]) and all participants achieved significant weight reduction (ΔBMI: -16.1 ± 5.6 kg/m2). Eleven of 16 participants (69%) reported taking the prescribed dietary supplements in the first year after MBS, but only five of them (31%) did so daily. In contrast to the high 12-month retention rate, follow-up after completion of the structured program was low at 24-months (9/16 [56%]) and at 36-months (5/15 [36%]), respectively. CONCLUSION: Participants demonstrated active decision making for or against MBS and high adherence with the structured pre- and 12 months post-MBS program, but participation was low thereafter. These findings endorse the need for longer term structured post-MBS programs to capture long-term outcomes and provide adequate care in this vulnerable group at the transition to adulthood.

Development and evaluation of a patient education programme for children, adolescents, and young adults with differences of sex development (DSD) and their parents: study protocol of Empower-DSD.

BACKGROUND: Differences in sexual development (DSD) are rare diseases, which affect the chromosomal, anatomical or gonadal sex differentiation. Although patient education is recommended as essential in a holistic care approach, standardised programmes are still lacking. The present protocol describes the aims, study design and methods of the Empower-DSD project, which developed an age-adapted multidisciplinary education programme to improve the diagnosis-specific knowledge, skills and empowerment of patients and their parents. METHODS: The new patient education programme was developed for children, adolescents and young adults with congenital adrenal hyperplasia, Turner syndrome, Klinefelter syndrome or XX-/or XY-DSD and their parents. The quantitative and qualitative evaluation methods include standardised questionnaires, semi-structured interviews, and participatory observation. The main outcomes (assessed three and six months after the end of the programme) are health-related quality of life, disease burden, coping, and diagnosis-specific knowledge. The qualitative evaluation examines individual expectations and perceptions of the programme. The results of the quantitative and qualitative evaluation will be triangulated. DISCUSSION: The study Empower-DSD was designed to reduce knowledge gaps regarding the feasibility, acceptance and effects of standardised patient education programmes for children and youth with DSD and their parents. A modular structured patient education programme with four generic and three diagnosis-specific modules based on the ModuS concept previously established for other chronic diseases was developed. The topics, learning objectives and recommended teaching methods are summarised in the structured curricula, one for each diagnosis and age group. At five study centres, 56 trainers were qualified for the implementation of the training programmes. A total of 336 subjects have been already enrolled in the study. The recruitment will go on until August 2022, the last follow-up survey is scheduled for February 2023. The results will help improve multidisciplinary and integrated care for children and youth with DSD and their families. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00023096 . Registered 8 October 2020 - Retrospectively registered.

Anti-adipogenic activity of maackiain and ononin is mediated via inhibition of PPARγ in human adipocytes.

Obesity is a global health burden for which we do not yet have effective treatments for prevention or therapy. Plants are an invaluable source of bioactive leads possessing anti-adipogenic potential. Ethnopharmacological use of Ononis spinosa L. roots (OSR) for treatment of obesity and metabolic disorders requires а scientific rationale. The current study examined the anti-adipogenic capacity of OSR and its secondary metabolites ononin (ONON) and maackiain (MACK) in human adipocytes as an in vitro model of obesity. Both ONON and MACK diminished lipid accumulation during adipocyte differentiation. Molecular docking analysis exposed the potential interactions between MACK or ONON and target regulatory adipogenic proteins. Furthermore, results from an RT-qPCR analysis disclosed significant upregulation of AMPK by MACK and ONON treatment. In addition, ONON increased SIRT1, PI3K and ACC mRNA expression, while MACK notably downregulated CEBPA, AKT, SREBP1, ACC and ADIPOQ. The protein level of PI3K, C/EBPα, PPARγ and adiponectin was reduced upon MACK treatment in a concentration-dependent manner. Similarly, ONON suppressed PI3K, PPARγ and adiponectin protein abundance. Finally, our study provides evidence that ONON exerts anti-adipogenic effect by upregulation of SIRT1 and inhibition of PI3K, PPARγ and adiponectin, while MACK induced strong inhibitory effect on adipogenesis via hampering PI3K, PPARγ/C/EBPα signaling and anti-lipogenic effect through downregulation of SREBP1 and ACC. Even though OSR does not hamper adipogenic differentiation, it could be exploited as a source of natural leads with anti-adipogenic potential. The multidirectional mechanism of action of MACK warrant further validation in the context of in vivo obesity models.

Coffee Bioactive N-Methylpyridinium Attenuates Tumor Necrosis Factor (TNF)-α-Mediated Insulin Resistance and Inflammation in Human Adipocytes.

Although coffee consumption has been historically associated with negative health outcomes, recent evidence suggests a lower risk of metabolic syndrome, obesity and diabetes among regular coffee drinkers. Among the plethora of minor organic compounds assessed as potential mediators of coffee health benefits, trigonelline and its pyrolysis product N-methylpyridinium (NMP) were preliminary shown to promote glucose uptake and exert anti-adipogenic properties. Against this background, we aimed at characterizing the effects of trigonelline and NMP in inflamed and dysfunctional human adipocytes. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with NMP or, for comparison, trigonelline, for 5 h before stimulation with tumor necrosis factor (TNF)-α. NMP at concentrations as low as 1 µmol/L reduced the stimulated expression of several pro-inflammatory mediators, including C-C Motif chemokine ligand (CCL)-2, C-X-C Motif chemokine ligand (CXCL)-10, and intercellular adhesion Molecule (ICAM)-1, but left the induction of prostaglandin G/H synthase (PTGS)2, interleukin (IL)-1ß, and colony stimulating factor (CSF)1 unaffected. Furthermore, NMP restored the downregulated expression of adiponectin (ADIPOQ). These effects were functionally associated with downregulation of the adhesion of monocytes to inflamed adipocytes. Under the same conditions, NMP also reversed the TNF-α-mediated suppression of insulin-stimulated Ser473 Akt phosphorylation and attenuated the induction of TNF-α-stimulated lipolysis restoring cell fat content. In an attempt to preliminarily explore the underlying mechanisms of its action, we show that NMP restores the expression of the master regulator of adipocyte differentiation peroxisome proliferator-activated receptor (PPAR)γ and downregulates activation of the pro-inflammatory mitogen-activated protein jun N-terminal kinase (JNK). In conclusion, NMP reduces adipose dysfunction in pro-inflammatory activated adipocytes. These data suggest that bioactive NMP in coffee may improve the inflammatory and dysmetabolic milieu associated with obesity.

Ziziphus jujuba Mill. leaf extract restrains adipogenesis by targeting PI3K/AKT signaling pathway.

The escalation in the global prevalence of obesity has focused attention on finding novel approaches for its management. Ziziphus jujuba Mill. (ZJL) leaf extract is reported as a traditional remedy for diverse pathological conditions, including obesity. The present study investigated whether ZJL affects adipogenic differentiation in human adipocytes. Additionally, following metabolite profiling of the extract, apigenin (APG), betulinic acid (BA) and maslinic acid (MA) were selected for biological activity evaluation. The possible interactions between APG, BA, MA and target proteins with a central role in adipogenesis were assessed through molecular docking. The potential mechanisms of ZJL, APG, BA and MA were identified using transcriptional analysis through real-time quantitative PCR and protein abundance evaluation by Western blotting. The obtained results revealed a concentration-dependent reduction of accumulated lipids after ZJL, BA and MA application. The key adipogenic transcription factors peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha (C/EBPα) were strongly decreased at a protein level by all treatments. Moreover, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway was found to be involved in the anti-adipogenic effect of ZJL, APG and BA. Collectively, our findings indicate that ZJL and its pure compounds hampered adipocyte differentiation through PI3K/AKT inhibition. Among the selected compounds, BA exhibits the most promising anti-adipogenic activity. Furthermore, being a complex mixture of phytochemicals, the ZJL extract could be utilized as source of yet unknown bioactive leads with potential implementation in obesity management.

Vitamin D supplementation after the second year of life: joint position of the Committee on Nutrition, German Society for Pediatric and Adolescent Medicine (DGKJ e.V.), and the German Society for Pediatric Endocrinology and Diabetology (DGKED e.V.).

BACKGROUND: Low vitamin D serum concentrations have been associated with rickets and other disorders in observational studies. Since vitamin D serum concentrations in children and adolescents are frequently below reference values, it is debated whether vitamin D should be supplemented after infancy. METHODS: The effects of vitamin D supplementation in children > 2 years of age are analyzed based on a literature review of randomized controlled trials (RCTs). RESULTS: Vitamin D supplementation can potentially reduce the risk for influenza infections and improve asthma bronchiale exacerbation; however, it has no impact on asthma bronchiale severity. Vitamin D supplementation has no relevant effect on attention-deficit/hyperactivity disorders, cardiac failure, hypertension, or incidence of type II diabetes mellitus. Vitamin D supplementation has no effect on the rate of multiple sclerosis relapses, but on the number of new lesions detected by MRI. For other endpoints, RCTs are lacking. CONCLUSION: Based on currently available studies, routine vitamin D supplementation is not be recommended for children aged > 2 years, even when they have serum concentrations below reference values. Routine vitamin D supplementation is not recommended in children who do not have risk factors and chronic diseases which are associated with calcium or vitamin D resorption disorders.

[Psychosocial Characteristic and Health Care for Unemployed Youths with Extreme Obesity - A Model Project]. / Psychosoziale Charakterisierung und Integrative Versorgung arbeitsloser Jugendlicher mit extremer Adipositas ­ ein Modellprojekt.

INTRODUCTION: In clinical care, unemployed youths have limited access to available obesity treatments including obesity surgery. With the implementation of a specialized obesity outpatient unit in cooperation with five German job-centers we aim to prove whether unemployed youths are interested in obesity treatment and how they adhere to a multilevel obesity treatment in terms of participation rates. MATERIALS AND METHODS: Youths (aged 15.0-24.9 years) with a body-mass-index (BMI) ≥30 kg/m2 were initially offered an individualized patient information concerning obesity treatment on the premises of the job-center. If interested, youths were included in the multicomponent treatment program (6 sessions). Those who participated in a minimum of 5 out of 6 treatment sessions were offered access to a preparation course (4 sessions) and an individualized evaluation of the indication for obesity surgery. RESULTS: Between 2012 and 2017, 83 youths (mean age 21.1 years, BMI 48.1 kg/m2, BMI 35.0-39.9 kg/m2: N=7, ≥40 kg/m2: N=71) were enrolled in the treatment program. 34 participated in ≥5/6 sessions in the multicomponent obesity treatment and 20 expressed an interest in obesity surgery. To date, 11 adolescents underwent obesity surgery with a mean BMI reduction of 14.3 kg/m2 between 3 and 36 months after obesity surgery (excess weight loss 27.3%) vs. 3.8 kg/m2 between 6 and 48 months after treatment initiation in the group of youths who did not receive obesity surgery. 13 youths were integrated in the primary labor market. DISCUSSION: Several unemployed youths accepted our treatment program and improved their health and vocational status in the course of their participation. CONCLUSIONS: The implementation of a specialized obesity outpatient unit within German job-centers is a successful strategy to characterize this high-risk-group and to determine their individual treatment needs. This finding must be confirmed with a larger sample size and by evaluating the long-term course of treatment.

Leptin Replacement Reestablishes Brain Insulin Action in the Hypothalamus in Congenital Leptin Deficiency.

OBJECTIVE: Human obesity is associated with impaired central insulin signaling, and in very rare cases, severe obesity can be caused by congenital leptin deficiency. In such patients, leptin replacement results in substantial weight loss and improvement in peripheral metabolism. RESEARCH DESIGN AND METHODS: In a leptin-deficient patient, we investigated the impact of leptin substitution on central insulin action, as quantified by changes in neuronal activity after intranasal insulin application. This was assessed before and during the first year of metreleptin substitution. RESULTS: After only 1 year, treatment with metreleptin reestablishes brain insulin sensitivity, particularly in the hypothalamus and, to a lesser degree, in the prefrontal cortex. Results are depicted in comparison with a control group. In our patient, brain activation changes were accompanied by substantial weight loss, reduced visceral adipose tissue, reduced intrahepatic lipid content, and improved whole-body insulin sensitivity. CONCLUSIONS: Leptin replacement and weight loss improved homeostatic insulin action in the patient in question.

Comprehensive molecular characterization of human adipocytes reveals a transient brown phenotype.

BACKGROUND: Functional brown adipose tissue (BAT), involved in energy expenditure, has recently been detected in substantial amounts in adults. Formerly overlooked BAT has now become an attractive anti-obesity target. METHODS AND RESULTS: Molecular characterization of human brown and white adipocytes, using a myriad of techniques including high-throughput RNA sequencing and functional assays, showed that PAZ6 and SW872 cells exhibit classical molecular and phenotypic markers of brown and white adipocytes, respectively. However, the pre-adipocyte cell line SGBS presents a versatile phenotype. A transit expression of classical brown markers such as UCP1 and PPARγ peaked and declined at day 28 post-differentiation initiation. Conversely, white adipocyte markers, including Tcf21, showed reciprocal behavior. Interestingly, leptin levels peaked at day 28 whereas the highest adiponectin mRNA levels were detected at day 14 of differentiation. Phenotypic analysis of the abundance and shape of lipid droplets were consistent with the molecular patterns. Accordingly, the oxidative capacity of SGBS adipocytes peaked on differentiation day 14 and declined progressively towards differentiation day 28. CONCLUSIONS: Our studies have unveiled a new phenotype of human adipocytes, providing a tool to identify molecular gene expression patterns and pathways involved in the conversion between white and brown adipocytes.

A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness.

OBJECTIVE: Leptin, a protein product of adipocytes, plays a critical role in the regulation of body weight, immune function, pubertal development, and fertility. So far, only three homozygous mutations in the leptin gene in a total of 13 individuals have been found leading to a phenotype of extreme obesity with marked hyperphagia and impaired immune function. DESIGN: Serum leptin was measured by ELISA. The leptin gene (OB) was sequenced in patient DNA. The effect of the identified novel mutation was assessed using HEK293 cells. RESULTS: We describe a 14-yr-old child of nonobese Austrian parents without known consanguinity. She had a body mass index of 31.5 kg/m(2) (+2.46 SD score) and undetectable leptin serum levels. Sequencing of the leptin gene revealed a hitherto unknown homozygous transition (TTA to TCA) in exon 3 of the LEP gene resulting in a L72S replacement in the leptin protein. RT-PCR, Western blot, and immunohistochemical analysis indicated that the mutant leptin was expressed in the patient's adipose tissue but retained within the cell. Using a heterologous cell system, we confirmed this finding and demonstrated that the side chain of Leu72 is crucial for intracellular leptin trafficking. Our patient showed signs of a hypogonadotropic hypogonadism. However, in contrast to the literature, she showed only mild obesity and a normal T cell responsiveness. CONCLUSIONS: These findings shed a new light on the clinical consequences of leptin deficiency. Congenital leptin deficiency should be considered possible in pediatric patients with mild obesity even if parents are lean and unrelated.