IMPROVE 2022 International Meeting on Pathway-Related Obesity: Vision of Excellence.

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany.

Dysfunction of the adhesion G protein-coupled receptor latrophilin 1 (ADGRL1/LPHN1) increases the risk of obesity.

Obesity is one of the diseases with severe health consequences and rapidly increasing worldwide prevalence. Understanding the complex network of food intake and energy balance regulation is an essential prerequisite for pharmacological intervention with obesity. G protein-coupled receptors (GPCRs) are among the main modulators of metabolism and energy balance. They, for instance, regulate appetite and satiety in certain hypothalamic neurons, as well as glucose and lipid metabolism and hormone secretion from adipocytes. Mutations in some GPCRs, such as the melanocortin receptor type 4 (MC4R), have been associated with early-onset obesity. Here, we identified the adhesion GPCR latrophilin 1 (ADGRL1/LPHN1) as a member of the regulating network governing food intake and the maintenance of energy balance. Deficiency of the highly conserved receptor in mice results in increased food consumption and severe obesity, accompanied by dysregulation of glucose homeostasis. Consistently, we identified a partially inactivating mutation in human ADGRL1/LPHN1 in a patient suffering from obesity. Therefore, we propose that LPHN1 dysfunction is a risk factor for obesity development.

Lipoprotein(a) serum concentrations in children in relation to body mass index, age and sex.

BACKGROUND: Lipoprotein(a) (Lp(a)) is an inherited risk factor for atherosclerotic cardiovascular disease (ASCVD). Limited data exist on Lp(a) values in children. We aimed to evaluate whether Lp(a) concentrations in youth are influenced by BMI. METHODS: 756 blood samples of 248 children with obesity and 264 matched healthy children aged 5 and 18 years, enrolled in the population-based LIFE Child (German civilization diseases cohort) study, were analyzed. Repeat measurements were available in 154 children (1-4 follow ups, ~1 year apart). RESULTS: The median Lp(a) concentration in the total cohort (n = 512) at first visit was 9.7 mg/dL (IQR 4.0-28.3). Lp(a) concentrations between 30-50 mg/dL were observed in 11.5%, while 12.5% exhibited Lp(a) ≧50 mg/dL. There was no association of Lp(a) with body mass index (BMI) (ß = 0.004, P = 0.49). Lp(a) levels did not correlate with age or sex, while Lp(a) was associated positively with low-density lipoprotein cholesterol (ß = 0.05, P < 0.0001). The Lp(a) risk category remained stable in 94% of all children in repeated measurements. CONCLUSIONS: The data showed no association of Lp(a) levels in children with BMI, age or sex. Measurement of Lp(a) in youth may be useful to identify children at increased lifetime risk for ASCVD. IMPACT: In youth, Lp(a) levels are not affected by age, sex and BMI. Lp(a) risk categories remain stable over time in repeated measurements in children. Measurement of Lp(a) in children may be useful as an additional factor to identify children at increased lifetime risk for ASCVD and for reverse family screening.

Clinical characteristics and outcomes of children, adolescents and young adults with overweight or obesity and mental health disorders.

BACKGROUND: Mental disorders are important comorbidities in youth with obesity. Aim was to describe the clinical characteristics and outcome of youth with overweight or obesity having comorbid mental disorders. METHODS: Data from children, adolescents, and young adults (age 6-30 years) with overweight or obesity and mental disorders (depression, anxiety disorder, eating disorder, attention deficit disorder (ADHD)) from 226 centers in Germany and Austria participating in the Adiposity Patient Registry (APV) were analyzed and compared with those without reported mental disorders using regression modeling. RESULTS: Mental health comorbidity was reported in a total of 3969 out of 114,248 individuals with overweight or obesity: 42.5% had ADHD, 31.3% anxiety disorders, 24.3% depression, and 12.9% eating disorders. Being male (OR 1.39 (95%CI 1.27;1.52)), of older age (1.42 (1.25;1.62)), or with extreme obesity (1.45 (1.30;1.63)) were most strongly associated with mental health comorbidity. Regression analysis showed that mean BMI-SDS was significantly higher in the group of individuals with depression and eating disorders (BMI-SDS 2.13 (lower; upper mean:2.09;2.16) and 2.22 (2.17;2.26)) compared to those without reported mental health comorbidity (BMI-SDS 2.008 (2.005;2.011); p < 0.001). In youth with ADHD, BMI-SDS was lower compared to those without reported mental disorders (BMI-SDS 1.91 (1.89;1.93) vs 2.008 (2.005;2.011); p < 0.001). Proportion of severe obesity was higher in individuals with depression (23.7%), anxiety disorders (17.8%), and eating disorders (33.3%), but lower in ADHD (10.3%), compared to those without reported mental disorders (13.5%, p < 0.002). Proportions of dyslipidaemia and abnormal carbohydrate metabolism were not different in youth with and without reported mental health comorbidity. BMI-SDS change after one year of lifestyle intervention program ranged between -0.22 and -0.16 and was similar in youth without and with different mental disorders. CONCLUSION: Health care professionals caring for youth with overweight or obesity should be aware of comorbid mental disorders and regular mental health screening should be considered.

Inhibition of AHCY impedes proliferation and differentiation of mouse and human adipocyte progenitor cells.

S-adenosyl-homocysteine-hydrolase (AHCY) plays an important role in the methionine cycle regulating cellular methylation levels. AHCY has been reported to influence proliferation and differentiation processes in different cell types, e.g. in cancer cells and mouse embryonic stem cells. In the development of adipose tissue, both the proliferation and differentiation of adipocyte progenitor cells (APCs) are important processes, which in the context of obesity are often dysregulated. To assess whether AHCY might also be involved in cell proliferation and differentiation of APCs, we investigated the effect of reduced AHCY activity on human and mouse APCs in vitro. We show that the inhibition of AHCY using adenosine dialdehyde (AdOx) and the knockdown of AHCY using gene-specific siRNAs reduced APC proliferation and number. Inhibition of AHCY further reduced APC differentiation into mature adipocytes and the expression of adipogenic differentiation markers. Global DNA methylation profiling in human APCs revealed that inhibition of AHCY is associated with alterations in CpG methylation levels of genes involved in fat cell differentiation and pathways related to cellular growth. Our findings suggest that AHCY is necessary for the maintenance of APC proliferation and differentiation and inhibition of AHCY alters DNA methylation processes leading to a dysregulation of the expression of genes involved in the regulation of these processes.

Epigenome-Wide Meta-analysis Reveals Associations Between Dietary Glycemic Index and Glycemic Load and DNA Methylation in Children and Adolescents of Different Body Sizes.

OBJECTIVE: Dietary glycemic index (GI) and glycemic load (GL) are associated with cardiometabolic health in children and adolescents, with potential distinct effects in people with increased BMI. DNA methylation (DNAm) may mediate these effects. Thus, we conducted meta-analyses of epigenome-wide association studies (EWAS) between dietary GI and GL and blood DNAm of children and adolescents. RESEARCH DESIGN AND METHODS: We calculated dietary GI and GL and performed EWAS in children and adolescents (age range: 4.5-17 years) from six cohorts (N = 1,187). We performed stratified analyses of participants with normal weight (n = 801) or overweight or obesity (n = 386). We performed look-ups for the identified cytosine-phosphate-guanine (CpG) sites (false discovery rate [FDR] <0.05) with tissue-specific gene expression of 832 blood and 223 subcutaneous adipose tissue samples from children and adolescents. RESULTS: Dietary GL was positively associated with DNAm of cg20274553 (FDR <0.05), annotated to WDR27. Several CpGs were identified in the normal-weight (GI: 85; GL: 17) and overweight or obese (GI: 136; GL: 298; FDR <0.05) strata, and none overlapped between strata. In participants with overweight or obesity, identified CpGs were related to RNA expression of genes associated with impaired metabolism (e.g., FRAT1, CSF3). CONCLUSIONS: We identified 537 associations between dietary GI and GL and blood DNAm, mainly in children and adolescents with overweight or obesity. High-GI and/or -GL diets may influence epigenetic gene regulation and thereby promote metabolic derangements in young people with increased BMI.

Identifying G protein-coupled receptors involved in adipose tissue function using the innovative RNA-seq database FATTLAS.

G protein-coupled receptors (GPCRs) modulate the function of adipose tissue (AT) in general and of adipocytes, specifically. Although it is well-established that GPCRs are widely expressed in AT, their repertoire as well as their regulation and function in (patho)physiological conditions (e.g., obesity) is not fully resolved. Here, we established FATTLAS, an interactive public database, for improved access and analysis of RNA-seq data of mouse and human AT. After extracting the GPCRome of non-obese and obese individuals, highly expressed and differentially regulated GPCRs were identified. Exemplarily, we describe four receptors (GPR146, MRGPRF, FZD5, PTGER2) and analyzed their functions in a (pre)adipocyte cell model. Besides all receptors being involved in adipogenesis, MRGPRF is essential for adipocyte viability and regulates cAMP levels, while GPR146 modulates adipocyte lipolysis via constitutive activation of Gi proteins. Taken together, by implementing and using FATTLAS we describe four hitherto unrecognized GPCRs associated with AT function and adipogenesis.

Who benefits most from outpatient lifestyle intervention? An IMI-SOPHIA study on pediatric individuals living with overweight and obesity.

OBJECTIVE: The first-line approach for childhood obesity is lifestyle intervention (LI); however, success varies. This study aimed first to identify distinct subgroups of response in children living with overweight and obesity and second to elucidate predictors for subclusters. METHODS: Based on the obesity patient follow-up registry the APV (Adipositas-Patienten-Verlaufsdokumentation) initiative, a total of 12,453 children and adolescents (median age: 11.5 [IQR: 9.7-13.2] years; BMI z score [BMIz]: 2.06 [IQR: 1.79-2.34]; 52.6% girls) living with overweight/obesity and participating in outpatient LI were studied. Longitudinal k-means clustering was used to identify individual BMIz response curve for up to 2 years after treatment initiation. Multinomial logistic regression was used to elucidate predictors for cluster membership. RESULTS: A total of 36.3% of children and adolescents experienced "no BMIz loss." The largest subcluster (44.8%) achieved "moderate BMIz loss," with an average delta-BMIz of -0.23 (IQR: -0.33 to -0.14) at study end. A total of 18.9% had a "pronounced BMIz loss" up to -0.61 (IQR: -0.76 to -0.49). Younger age and lower BMIz at LI initiation, larger initial BMIz loss, and less social deprivation were linked with higher likelihood for moderate or pronounced BMIz loss compared with the no BMIz loss cluster (all p < 0.05). CONCLUSIONS: These results support the importance of patient-tailored intervention and earlier treatment escalation in high-risk individuals who have little chance of success.

Fasting indices of glucose-insulin-metabolism across life span and prediction of glycemic deterioration in children with obesity from new diagnostic cut-offs.

Background: Fasting indices of glucose-insulin-metabolism are an easy and affordable tool to assess insulin resistance. We aimed to establish reference ranges for fasting insulin indices that reflect age-dependent variation over the entire life span and subsequently test their clinical application regarding the prediction of glycemic deterioration in children. Methods: We calculated age- and puberty-dependent reference values for HOMA-IR, HOMA2-IR, HOMA-ß, McAuley index, fasting insulin, and fasting glucose from 6994 observations of 5512 non-obese healthy subjects aged 5-80 years. Applying those references, we determined the prevalence of insulin resistance among 2538 subjects with obesity. Furthermore, we investigated the intraindividual stability and the predictive values for future dysglycemia of these fasting indices in 516 children and adolescents with obesity up to 19 years of follow-up. We validated the results in three independent cohorts. Findings: There was a strong age-dependent variation of all indices throughout the life span, including prolonged recovery of pubertal insulin resistance and a subsequent continuous increase throughout adulthood. Already from age 5 years onwards, >40% of children with obesity presented with elevated parameters of insulin resistance. Applying newly developed reference ranges, insulin resistance among children with obesity doubled the risk for future glycemic deterioration (HOMA-IR HR 1.88 (95% CI 1.1-3.21)), fasting insulin HR 1.89 (95% CI 1.11-3.23). In contrast, fasting glucose alone was not predictive for emerging dysglycemia in children with obesity (HR 1.03 (95% CI 0.62-1.71)). The new insulin-based thresholds were superior to fasting glucose and HbA1c in detecting children eventually manifesting with dysglycemia in prospective analyses. Interpretation: The variation of fasting glucose-insulin-metabolism across the life span necessitates age-specific reference ranges. The improved prediction of future glycemic deterioration by indices based on fasting insulin beyond simple glucose measures alone could help to stratify risk characteristics of children with obesity in order to guide patient-tailored prevention and intervention approaches. Funding: German Research Foundation (DFG)-through SFB 1052, project number 209933838, subproject C5; Federal Ministry of Education and Research, Germany; European Union-European Regional Development Fund; Free State of Saxony. The German Diabetes Association, the CarbHealth consortium (01EA1908B). EU-IMI2-Consortium SOPHIA (grant agreement No 875534), German Center for Diabetes Research (DZD), grant number 82DZD14E03.

Sex hormones associated with temporomandibular pain on palpation in male adolescents-Results of the epidemiologic LIFE child study.

OBJECTIVE: This study aimed to investigate whether the sex steroid precursor hormone dehydroepiandrosterone sulphate (DHEA-S), sex hormone-binding globulin (SHBG) and testosterone (TT) are associated with temporomandibular (TM) pain on palpation in male adolescents. METHODS: Out of the LIFE Child study dataset containing 1022 children and adolescents aged 10-18 years (496 males, 48.5%), we used a subsample of 273 male adolescents (mean age: 13.8 ± 2.3 years) in advanced pubertal development (PD) to analyse the association between hormones and TM pain. The Tanner scale was applied to describe the stage of PD. Pain on palpation of the temporalis and masseter muscles and the TM joints (palpation pain) was assessed using the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). Serum levels of sex hormones (DHEA-S, SHBG and TT) were determined using standardised laboratory analyses. Free TT was estimated from the ratio between TT and SHBG (free androgen index[FAI]). We calculated the risk of perceived positive palpation pain for male participants as a function of hormone levels (DHEA-S, FAI) taking into account age and body mass index (BMI). RESULTS: Among more developed (Tanner stage 4-5) male adolescents, 22.7% (n = 62) reported palpation pain in the TM region. In these participants, FAI levels were approximately half that of individuals without such pain (p < .01). DHEA-S levels were about 30% lower in the pain group (p < .01). In multivariable regression analyses, the odds ratio (OR) for pain on palpation decreased to 0.75 (95% confidence interval [CI]: 0.57-0.98) per 10 units of FAI level compared to those without pain, after controlling for the effects of age and adjusted BMI. We observed the same effect for this subgroup per unit of DHEA-S serum level (OR = 0.71; 95% CI: 0.53-0.94). CONCLUSION: At subclinical lower levels of serum free TT and DHEA-S, male adolescents are more likely to report pain on standardised palpation of the masticatory muscles and/or TM joints. This finding supports the hypothesis that sex hormones may influence pain reporting.

Reducing BMI below the obesity threshold in adolescents treated with once-weekly subcutaneous semaglutide 2.4 mg.

OBJECTIVE: The aim of this study was to examine how improvement in BMI with the glucagon-like peptide-1 receptor agonist semaglutide translated to changes in BMI category in a post hoc analysis of the double-blind, phase 3a randomized controlled Semaglutide Treatment Effect in People with obesity (STEP) TEENS trial. METHODS: Adolescents with obesity received once-weekly subcutaneous semaglutide 2.4 mg or placebo plus lifestyle intervention, which comprised counseling in healthy nutrition and a goal of 60 minutes of moderate- to high-intensity physical activity per day. Achievement of an improvement in BMI category and attainment of normal-weight or overweight BMI by week 68 were analyzed using logistic regression models. RESULTS: In the overall population, 44.9% of participants receiving semaglutide achieved weight reduction resulting in reclassification to a normal-weight or overweight BMI category versus 12.1% receiving placebo at week 68 (odds ratio: 22.7; 95% CI: 7.6-67.9). The proportion of semaglutide-treated participants in obesity class III decreased from 37.3% to 13.6% but increased with placebo. The odds ratio for achieving an improvement of at least one BMI category was significantly greater with semaglutide versus placebo (23.5; 95% CI: 9.9-55.5); an improvement of at least one BMI category was seen in 73.7% of participants receiving semaglutide compared with 19.0% of participants receiving placebo. CONCLUSIONS: Semaglutide was highly effective in reducing BMI category. While on treatment, most trial participants' BMI improved by at least one category, and >40% reached a category below the obesity threshold.

Is COVID-19 to Blame? Trends of Incidence and Sex Ratio in Youth-Onset Type 2 Diabetes in Germany.

OBJECTIVE: We investigated the incidence of pediatric type 2 diabetes (T2D) in Germany during 2 years of the coronavirus disease 2019 (COVID-19) pandemic (2020-2021) compared with the control period 2011-2019. RESEARCH DESIGN AND METHODS: Data on T2D in children (aged 6 to <18 years) were obtained from the DPV (German Diabetes Prospective Follow-up) Registry. Poisson regression was used to estimate incidences for 2020 and 2021 based on data from 2011 to 2019, and these were compared with observed incidences in 2020 and 2021 by estimating incidence rate ratios (IRRs) with 95% CIs. RESULTS: Incidence of youth-onset T2D increased from 0.75 per 100,000 patient-years (PYs) in 2011 (95% CI 0.58, 0.93) to 1.25 per 100,000 PYs in 2019 (95% CI 1.02, 1.48), an annual increase of 6.8% (95% CI 4.1, 9.6). In 2020, T2D incidence increased to 1.49 per 100,000 PYs (95% CI 1.23, 1.81), which was not significantly higher than predicted (IRR 1.15; 95% CI 0.90, 1.48). In 2021, the observed incidence was significantly higher than expected (1.95; 95% CI 1.65, 2.31 vs. 1.38; 95% CI 1.13, 1.69 per 100,000 PYs; IRR 1.41; 95% CI 1.12, 1.77). Although there was no significant increase in incidence in girls in 2021, the observed incidence in boys (2.16; 95% CI 1.73, 2.70 per 100,000 PYs) significantly exceeded the predicted rate (IRR 1.55; 95% CI 1.14, 2.12), leading to a reversal of the sex ratio of pediatric T2D incidence. CONCLUSIONS: In Germany, incidence of pediatric T2D increased significantly in 2021. Adolescent boys were more affected by this increase, resulting in a reversal of the sex ratio of youth-onset T2D.

COBL, MKX and MYOC Are Potential Regulators of Brown Adipose Tissue Development Associated with Obesity-Related Metabolic Dysfunction in Children.

Obesity is already accompanied by adipose tissue (AT) dysfunction and metabolic disease in children and increases the risk of premature death. Due to its energy-dissipating function, brown AT (BAT) has been discussed as being protective against obesity and related metabolic dysfunction. To analyze the molecular processes associated with BAT development, we investigated genome-wide expression profiles in brown and white subcutaneous and perirenal AT samples of children. We identified 39 upregulated and 26 downregulated genes in uncoupling protein 1 (UCP1)-positive compared to UCP1-negative AT samples. We prioritized for genes that had not been characterized regarding a role in BAT biology before and selected cordon-bleu WH2 repeat protein (COBL), mohawk homeobox (MKX) and myocilin (MYOC) for further functional characterization. The siRNA-mediated knockdown of Cobl and Mkx during brown adipocyte differentiation in vitro resulted in decreased Ucp1 expression, while the inhibition of Myoc led to increased Ucp1 expression. Furthermore, COBL, MKX and MYOC expression in the subcutaneous AT of children is related to obesity and parameters of AT dysfunction and metabolic disease, such as adipocyte size, leptin levels and HOMA-IR. In conclusion, we identify COBL, MKX and MYOC as potential regulators of BAT development and show an association of these genes with early metabolic dysfunction in children.

Single Point Insulin Sensitivity Estimator (SPISE) As a Prognostic Marker for Emerging Dysglycemia in Children with Overweight or Obesity.

The single point insulin sensitivity estimator (SPISE) is a recently developed fasting index for insulin sensitivity based on triglycerides, high density lipoprotein cholesterol, and body mass index. SPISE has been validated in juveniles and adults; still, its role during childhood remains unclear. To evaluate the age- and sex-specific distribution of SPISE, its correlation with established fasting indexes and its application as a prognostic marker for future dysglycemia during childhood and adolescence were assessed. We performed linear modeling and correlation analyses on a cross-sectional cohort of 2107 children and adolescents (age 5 to 18.4 years) with overweight or obesity. Furthermore, survival analyses were conducted upon a longitudinal cohort of 591 children with overweight/obesity (1712 observations) with a maximum follow-up time of nearly 20 years, targeting prediabetes/dysglycemia as the end point. The SPISE index decreased significantly with age (−0.34 units per year, p < 0.001) among children and adolescents with overweight and obesity. Sex did not have an influence on SPISE. There was a modest correlation between SPISE and established fasting markers of insulin resistance (R = −0.49 for HOMA-IR, R = −0.55 for QUICKI-IR). SPISE is a better prognostic marker for future dysglycemia (hazard ratio (HR) 3.47, 95% confidence interval (CI) 1.60−7.51, p < 0.01) than HOMA-IR and QUICKI-IR (HR 2.44, 95% CI 1.24−4.81, p < 0.05). The SPISE index is a surrogate marker for insulin resistance predicting emerging dysglycemia in children with overweight or obesity, and could, therefore, be applied to pediatric cohorts that lack direct insulin assessment.

Health relevance of lowering postprandial glycaemia in the paediatric population through diet': results from a multistakeholder workshop.

To summarize current knowledge and gaps regarding the role of postprandial glycaemic response in the paediatric population, a workshop was organized in June 2021 by the European branch of the International Life Science Institute (ILSI). This virtual event comprised of talks given by experts followed by in-depth discussions in breakout sessions with workshop participants. The main pre-specified topics addressed by the workshop organizing committee to the invited speakers and the workshop participants were: (1) the role of glycaemic responses for paediatric health, based on mechanistic insights from animal and human data, and long-term evidence from observational and intervention studies in paediatric populations, and (2) changes in metabolism and changes in dietary needs from infancy to adolescence. Each talk as well as the discussions were summarised, including the main identified research gaps. The workshop led to the consensus on the crucial role on health of postprandial glycaemic response in paediatric population. However, a lack of scientific data has been identified regarding detailed glucose and insulin profiles in response to foods commonly consumed by paediatric populations, as well as a lack of long-term evidence including the need for suitable predictors during childhood and adolescence to anticipate health effects during adulthood.

CD248 induces a maladaptive unfolded protein response in diabetic kidney disease.

Dysfunction of mesangial cells plays a major role in the pathogenesis of diabetic kidney disease (DKD), the leading cause of kidney failure. However, the underlying molecular mechanisms are incompletely understood. By unbiased gene expression analysis of glucose-exposed mesangial cells, we identified the transmembrane receptor CD248 as the most upregulated gene, and the maladaptive unfolded protein response (UPR) as one of the most stimulated pathways. Upregulation of CD248 was further confirmed in glucose-stressed mesangial cells in vitro, in kidney glomeruli isolated from diabetic mice (streptozotocin; STZ and db/db models, representing type 1 and type 2 diabetes mellitus, respectively) in vivo, and in glomerular kidney sections from patients with DKD. Time course analysis revealed that glomerular CD248 induction precedes the onset of albuminuria, mesangial matrix expansion and maladaptive UPR activation (hallmarked by transcription factor C/EBP homologous protein (CHOP) induction) but is paralleled by loss of the adaptive UPR regulator spliced X box binding protein (XBP1). Mechanistically, CD248 promoted maladaptive UPR signaling via inhibition of the inositol requiring enzyme 1α (IRE1α)-mediated transcription factor XBP1 splicing in vivo and in vitro. CD248 induced a multiprotein complex comprising heat shock protein 90, BH3 interacting domain death agonist (BID) and IRE1α, in which BID impedes IRE1α-mediated XBP1 splicing and induced CHOP mediated maladaptive UPR signaling. While CD248 knockout ameliorated DKD-associated glomerular dysfunction and reverses maladaptive unfolded protein response signaling, concomitant XBP1 deficiency abolished the protective effect in diabetic CD248 knockout mice, supporting a functional interaction of CD248 and XBP1 in vivo. Hence, CD248 is a novel mesangial cell receptor inducing maladaptive UPR signaling in DKD.

Stress, Stress Reduction and Obesity in Childhood and Adolescence.

BACKGROUND: Obesity in childhood and adolescence remains a great global health challenge. Stress exposure during childhood and adolescence is associated with a higher risk for obesity, yet the linkage between stress and obesity is multidimensional, and its biological and behavioral mechanisms are still not fully understood. SUMMARY: In this literature review, we identified different types of stress exposure in children and adolescents, including first studied effects of the COVID-19 pandemic as a prolonged stress exposure and their association with obesity risk. We investigated studies on the connection of altered stress biology and behavioral pathways as well as intervention programs on stress reduction in children and adolescents with obesity. KEY MESSAGES: There is evidence that stress exposure in childhood and adolescence promotes biological and behavioral alterations that contribute to the multifactorial pathogenesis of obesity. COVID-19 related-stress presents the most current example of a negative influence on weight development in children and adolescents. However, longitudinal studies on the linkage between environmental, behavioral, and biological factors across development are few, and results are partly equivocal. Intervention programs to reduce stress in children through mindfulness might be a promising adjunctive tool in the prevention and treatment of childhood and adolescent obesity that could further offer proof of concept of theoretically elaborated cause-and-effect relationships.