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Maternal prepregnancy obesity is an important risk factor for offspring obesity, which may partially operate through prenatal programming mechanisms.The study aimed to systematically identify prenatal metabolomic profiles mediating the intergenerational transmission of obesity.We included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study (CANDLE) pregnancy cohort. Liquid chromatography-mass spectrometry was used to conduct metabolomic profiling on the maternal plasma samples of the second trimester. The childhood growth outcomes of interest included body mass index (BMI) trajectories from birth to age 4 (rising-high-, moderate-, and low-BMI trajectories) as well as overweight/obesity (OWO) risk at age 4. Mediation analysis was conducted to identify metabolite mediators linking maternal OWO and childhood growth outcomes. The potential causal effects of maternal OWO on metabolite mediators were examined using the Mendelian Randomization (MR) method.Among 880 metabolites detected in the maternal plasma during pregnancy, 14 and 11 metabolites significantly mediated the effects of maternal prepregnancy OWO on childhood BMI trajectories and the OWO risk at age 4, respectively, and five of those mediated both outcomes. The MR analysis suggested six of the 20 prenatal metabolite mediators might be causally influenced by maternal prepregnancy OWO, most of which are from the pathways related to the metabolism of amino acids (hydroxyasparagine, glutamate, and homocitrulline), sterols (campesterol), and nucleotides (N2, N2-dimethylguanosine).Our study provided further evidence that prenatal metabolomic profiles might mediate the effect of maternal OWO on early childhood growth trajectories and OWO risk in offspring. The metabolic pathways including identified metabolite mediators might provide novel intervention targets for preventing the intrauterine development of obesity in offspring of mothers with obesity.

Objective Prenatal metabolomics profiles, providing measures of in utero nutritional and environmental exposures, may improve the prediction of childhood outcomes. We aimed to identify prenatal plasma metabolites associated with early childhood body mass index (BMI) trajectories and overweight/obesity risk in offspring. Methods This study included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study. An untargeted metabolomics analysis was performed on the mothers' plasma samples collected during the second trimester. The children's BMI-z-score trajectories from birth to age 4 [rising-high- (9.8%), moderate- (68.2%), and low-BMI (22.0%)] and overweight/obesity status at age 4 were the main outcomes. The least absolute shrinkage and selection operator (LASSO) was used to select the prenatal metabolites associated with childhood outcomes. Results The mothers were 24.5 years old on average at recruitment, 76.4% having education less than 12 years and 80.0% with Medicaid or Medicare. In LASSO, seven and five prenatal metabolites were associated with the BMI-z-score trajectories and overweight/obese at age 4, respectively. These metabolites are mainly from/relevant to the pathways of steroid biosynthesis, amino acid metabolism, vitamin B complex, and xenobiotics metabolism (e.g., caffeine and nicotine). The odds ratios (95% CI) associated with a one SD increase in the prenatal metabolite risk scores (MRSs) constructed from the LASSO-selected metabolites were 2.97 (1.95-4.54) and 2.03 (1.54-2.67) for children being in the rising-high-BMI trajectory group and overweight/obesity at age 4, respectively. The MRSs significantly improved the risk prediction for childhood outcomes beyond traditional prenatal risk factors. The increase (95% CI) in the area under the receiver operating characteristic curves were 0.10 (0.03-0.18) and 0.07 (0.02-0.12) for the rising-high-BMI trajectory (P = 0.005) and overweight/obesity at age 4 (P = 0.007), respectively. Conclusions Prenatal metabolomics profiles advanced prediction of early childhood growth trajectories and obesity risk in offspring.

Context Pediatric obesity is a serious health problem in the United States. While lifestyle modification therapy with dietary changes and increased physical activity are integral for the prevention and treatment of mild to moderate obesity in youth, only a modest effect on sustained weight reduction is observed in children and young adults with severe obesity. This underscores the need for additional evidence-based interventions for children and adolescents with severe obesity, including pharmacotherapy, before considering invasive procedures such as bariatric surgery. Evidence Acquisition This publication focuses on recent advances in pharmacotherapy of obesity with an emphasis on medications approved for common and rarer monogenic forms of pediatric obesity. Evidence Synthesis We review medications currently available in the United States, both those approved for weight reduction in children and “off-label” medications that have a broad safety margin. Conclusion It is intended that this review will provide guidance for practicing clinicians and will encourage future exploration for successful pharmacotherapy and other interventions for obesity in youth.

Bile acid receptors regulate the metabolic and immune functions of circulating enterohepatic bile acids. This process is disrupted by administration of parenteral nutrition (PN), which may induce progressive hepatic injury for unclear reasons, especially in the newborn, leading to PN-associated liver disease. To explore the role of bile acid signaling on neonatal hepatic function, we initially observed that Takeda G protein receptor 5 (TGR5)-specific bile acids were negatively correlated with worsening clinical disease markers in the plasma of human newborns with prolonged PN exposure. To test our resulting hypothesis that TGR5 regulates critical liver functions to PN exposure, we used TGR5 receptor deficient mice (TGR5−/−). We observed PN significantly increased liver weight, cholestasis, and serum hepatic stress enzymes in TGR5−/− mice compared with controls. Mechanistically, PN reduced bile acid synthesis genes in TGR5−/−. Serum bile acid composition revealed that PN increased unconjugated primary bile acids and secondary bile acids in TGR5−/− mice, while increasing conjugated primary bile acid levels in TGR5-competent mice. Simultaneously, PN elevated hepatic IL-6 expression and infiltrating macrophages in TGR5−/− mice. However, the gut microbiota of TGR5−/− mice compared with WT mice following PN administration displayed highly elevated levels of Bacteroides and Parabacteroides, and possibly responsible for the elevated levels of secondary bile acids in TGR5−/− animals. Intestinal bile acid transporters expression was unchanged. Collectively, this suggests TGR5 signaling specifically regulates fundamental aspects of liver bile acid homeostasis during exposure to PN. Loss of TGR5 is associated with biochemical evidence of cholestasis in both humans and mice on PN. NEW & NOTEWORTHY Parenteral nutrition is associated with deleterious metabolic outcomes in patients with prolonged exposure. Here, we demonstrate that accelerated cholestasis and parental nutrition-associated liver disease (PNALD) may be associated with deficiency of Takeda G protein receptor 5 (TGR5) signaling. The microbiome is responsible for production of secondary bile acids that signal through TGR5. Therefore, collectively, these data support the hypothesis that a lack of established microbiome in early life or under prolonged parenteral nutrition may underpin disease development and PNALD.

Alström syndrome (AS) is a rare multi-system disorder for which early-onset childhood obesity is a cardinal feature. Like humans with AS, animal models withAlms1loss-of-function mutations develop obesity, supporting the notion that ALMS1/Alms1 is required for the regulatory control of energy balance across species. This study aimed to determine which component(s) of energy balance are reliant on Alms1. Here, we performed comprehensive energy balance phenotypingAlms1tvrm102mice at both eight- and eighteen-weeks-of-age. We found that adiposity gains occurred early and rapidly inAlms1tvrm102male mice but much later in females. Rapid increases in body fat in males was due to a marked reduction in energy expenditure (EE) during early life and not due to any genotype-specific increases in energy intake under chow conditions. Energy intake did increase in a genotype-specific manner when mice were provided a high-fat-diet, exacerbating the effects of reduced EE on obesity progression. The EE deficit observed in maleAlms1tvrm102mice did not persist as mice aged, suggesting loss of Alms1 either causes a developmental delay in the mechanisms controlling early life EE, or that activation of compensatory mechanisms occurs after obesity is established. Future studies will determine how ALMS1/Alms1 modulates EE and how sex moderates this process.

BackgroundAdherence to dietary interventions is a significant barrier in the treatment of childhood obesity. Time-limited eating (TLE) is a simple dietary approach that limits food intake to a given number of consecutive hours per day, but parental and youth acceptability of TLE in youth with obesity is unknown. This study explored the feasibility of utilizing TLE among parents and youth attending pediatric weight management (PWM).MethodsMembers of COMPASS (Childhood Obesity Multi-Program Analysis and Study System) developed a survey to assess the acceptability of TLE in families attending PWM, which included patient characteristics, current diet and sleep schedules, and interests in trying TLE. The survey was administered electronically via REDCap or manually to parents of patients between the ages of 8-17 years old and to patients 11-17 years old attending one of five PWM practices in the COMPASS network.ResultsPatients (n=213) were 13.0 ± 2.5 years old, 58% female, 52% White, 22% Black, 17% Hispanic/Latino, and 47% reported a diagnosed psychological disorder. On average, parents reported their child’s daily eating spanned 12.5 ± 1.9 hours (7:35am - 8:05pm) and included 5.6 ± 1.6 eating bouts (meals + snacks). Most parents reported being likely to try TLE ≤12 hours/d (TLE12: 66%), which was similar to the likelihood of following a nutrient-balanced diet (59%). Likelihood was lower for TLE ≤10 hours/d (TLE10: 39%) or ≤8 hours/d (TLE8: 26%) (pConclusionsTwo-thirds of parents with children attending PWM programs report interest in TLE ≤12 hours/d regardless of demographic characteristics, but interest wanes when limiting eating to ≤10 or ≤8 hours per day. Time-limited eating appears to be a feasible option in PWM settings provided treatment options are individualized based on the interests and barriers of patients and their families.

Energy metabolism in the heart is affected during states of dysfunction. Understanding how the heart utilizes substrates in cardiomyopathy may be key to the development of alternative treatment modalities. Myocardial insulin resistance has been proposed as a possible barrier to effective glucose metabolism in the heart. Extensive literature on the topic in adult individuals exists; however, review in the pediatric population is sparse. The pathophysiology of disease in children and adolescents is unique. The aim of this paper is to review the current knowledge on insulin resistance in dilated cardiomyopathy while also filling the gap when considering care in the pediatric population.

Background This study evaluates implementation of an orientation session to address a waitlist of more than 2000 referrals to a pediatric weight management clinic in the Mid-South United States. Methods An hour-long group-based orientation to the pediatric weight management clinic was implemented to provide information about the structure and expectations of the clinic as well as education on healthy lifestyle recommendations. Families were contacted from the waitlist by telephone and invited to attend an orientation session prior to scheduling a clinic appointment. Results Of 2251 patients contacted from the waitlist, 768 scheduled an orientation session, of which 264 (34 %) attended. Of the 264 orientation participants, 246 (93 %) scheduled a clinic appointment. Of those, 193 (79 %) completed a clinic visit. Waitlist times decreased from 297.8 ± 219.4 days prior to implementation of orientation sessions to 104.1 ± 219.4 days after. Conclusions Orientation has been an effective and efficient way to triage patient referrals while maximizing attendance in limited clinic slots for patients and families demonstrating interest and motivation. Elements of this approach are likely generalizable to other pediatric clinical settings that must strategically manage a large volume of patient referrals.

Brain-derived neurotrophic factor (BDNF), a key peptide in neurocognitive development, has been reported to be elevated in the serum of children with autism spectrum disorder (ASD). In a few studies, however, no differences or the converse have been documented. As a secondary analysis of a natural history study, we examined differences in ELISA serum BDNF between a group of children aged 1 to 9 years (69% white) with ASD (n = 94) and those with typical development (n = 52) or non-ASD developmental delay (n = 21), while accounting for the potential confounding effects of platelet quantity. Platelet counts were measured within 4 h of blood draw using an automated cell counter. Taqman single nucleotide polymorphism (SNP) assays were used to genotype 11 SNPs within the BDNF locus. Unadjusted mean BDNF concentration was higher in children with ASD than in children with typical development (standardized mean difference = 0.23; 95% CI 0.07, 0.38), but not children with non-ASD developmental delay. The magnitude of this difference was reduced after adjusting for platelet count (standardized mean difference = 0.18; 95% CI 0.02, 0.33). Although some BDNF SNPs were related to BDNF concentration, the distributions of these genotypes did not differ across diagnostic groups. This study replicates previous work suggesting that average serum BDNF concentration is higher in ASD compared to typical development, and extends that work by highlighting the potentially confounding role of platelet counts. The etiology of platelet count differences warrants further elucidation. Nonetheless, our results suggest that elevation in BDNF may be partially explained by higher platelet counts in children with ASD, an association that should be considered in future analysis and interpretation.Registration: NCT00298246

Rare pain insensitive individuals offer unique insights into how pain circuits function, and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, range of intellectual disabilities) syndrome, who have variably-sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing (QST), demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ and C-fiber mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber mediated cold responses and cold avoidance on a cold plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that heterozygous deletion of the BDNF gene reduces pain sensitivity, and establish BDNF as a determinant of nociceptive sensitivity.

Youth with obesity are more likely than normal-weight peers to experience psychosocial problems. Empirically-based recommendations for addressing pediatric obesity include intensive interdisciplinary weight management comprising medical, behavioral health, nutrition, and exercise components. The present study examined changes in psychosocial functioning associated with frequency of participation in an interdisciplinary pediatric weight management program. Participants were 86 patients (55.8% females; median age = 11.5 years; 67.4% Non-Hispanic Black; median BMI percentile = 99.5) enrolled in an interdisciplinary pediatric weight management program for at least one year. Psychosocial functioning was measured with the Pediatric Symptom Checklist (PSC-17), a caregiver-completed mental health screen that assesses internalizing, externalizing, and attention difficulties as well as global functioning. The PSC-17 was completed at the initial clinic visit (baseline) and repeated one-year later (annual). The Wilcoxon Signed Rank test indicated that annual PSC-17 scores were significantly lower than baseline scores across all domains. Spearman correlation coefficients revealed no significant association between total number of clinic visits and PSC-17 global or subscale scores. However, the number of visits for exercise-only sessions was significantly correlated with caregiver-reported improvement in internalizing behaviors. Findings suggest that participation in interdisciplinary pediatric weight management may improve psychosocial functioning in youth with obesity and that attending supervised exercise sessions may be especially beneficial for improving internalizing behavior symptoms.

BackgroundWe investigated the individual and additive effects of three modifiable maternal metabolic factors, including pre-pregnancy overweight/obesity, gestational weight gain (GWG), and gestational diabetes mellitus (GDM), on early childhood growth trajectories and obesity risk.MethodsA total of 1425 mother-offspring dyads (953 black and 472 white) from a longitudinal birth cohort were included in this study. Latent class growth modeling was performed to identify the trajectories of body mass index (BMI) from birth to 4 years in children. Poisson regression models were used to examine the associations between the maternal metabolic risk factors and child BMI trajectories and obesity risk at 4 years.ResultsWe identified three discrete BMI trajectory groups, characterized as rising-high-BMI (12.6%), moderate-BMI (61.0%), or low-BMI (26.4%) growth. Both maternal pre-pregnancy obesity (adjusted relative risk [adjRR] = 1.96; 95% confidence interval [CI]: 1.36-2.83) and excessive GWG (adjRR = 1.71, 95% CI: 1.13-2.58) were significantly associated with the rising-high-BMI trajectory, as manifested by rapid weight gain during infancy and a stable but high BMI until 4 years. All three maternal metabolic indices were significantly associated with childhood obesity at age 4 years (adjRR for pre-pregnancy obesity = 2.24, 95% CI: 1.62-3.10; adjRR for excessive GWG = 1.46, 95% CI: 1.01-2.09; and adjRR for GDM = 2.14, 95% = 1.47-3.12). In addition, risk of rising-high BMI trajectory or obesity at age 4 years was stronger among mothers with more than one metabolic risk factor. We did not observe any difference in these associations by race.ConclusionMaternal pre-pregnancy obesity, excessive GWG, and GDM individually and jointly predict rapid growth and obesity at age 4 years in offspring, regardless of race. Interventions targeting maternal obesity and metabolism may prevent or slow the rate of development of childhood obesity.

Background A phase 2 trial has suggested that treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide is associated with a decrease in hunger and weight-related outcomes in participants with Bardet-Biedl syndrome (BBS) and Alstrom syndrome. Here, we present the study design of an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial to assess the long-term efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS or Alstrom syndrome ( ClinicalTrials.gov identifier: NCT03746522). Methods It was initially planned that ~30 participants aged ≥6 years with a clinical diagnosis of BBS or Alstrom syndrome would be enrolled. Participants with obesity as defined by a body mass index ≥30 kg/m2 (in those aged ≥16 years) or a weight >97th percentile (in those aged 6–15 years) are included. Participants are initially randomized in a 1:1 ratio to receive setmelanotide or placebo for 14 weeks (period 1). Following period 1, all participants receive 38 weeks of open-label treatment with setmelanotide (period 2). In each treatment period, setmelanotide is administered at 3 mg once a day following completion of dose escalation. The primary endpoint is the proportion of participants aged ≥12 years achieving a clinically meaningful reduction from baseline (≥10%) in body weight after ~52 weeks (eg, following period 2). Safety and tolerability are assessed by frequency of adverse events. Conclusions This pivotal trial is designed to evaluate the efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS and Alstrom syndrome. Submission category Study Design, Statistical Design, Study Protocols.

Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data.

Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

As an active interface between the host and their diet, the gut microbiota influences host metabolic adaptation; however, the contributions of fungi have been overlooked. Here, we investigate whether variations in gut mycobiome abundance and composition correlate with key features of host metabolism. We obtained animals from four commercial sources in parallel to test if differing starting mycobiomes can shape host adaptation in response to processed diets. We show that the gut mycobiome of healthy mice is shaped by the environment, including diet, and significantly correlates with metabolic outcomes. We demonstrate that exposure to processed diet leads to persistent differences in fungal communities that significantly associate with differential deposition of body mass in male mice compared to mice fed standardized diet. Fat deposition in the liver, transcriptional adaptation of metabolically active tissues and serum metabolic biomarker levels are linked with alterations in fungal community diversity and composition. Specifically, variation in fungi from the genera Thermomyces and Saccharomyces most strongly associate with metabolic disturbance and weight gain. These data suggest that host–microbe metabolic interactions may be influenced by variability in the mycobiome. This work highlights the potential significance of the gut mycobiome in health and has implications for human and experimental metabolic studies. Tahliyah S. Mims et al. investigate the influence of the gut mycobiome abundance and composition on host metabolism. Using mice from four different commercial suppliers they find that the gut mycobiome is shaped by diet, and that abundance and composition correlate with key metabolic features. In particular they find that Thermomyces and Saccharomyces species most strongly associate with weight gain.

Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data., How neurodevelopmental disorder-associated risk genes are translated into spatially patterned brain vulnerabilities is unclear. Here, the authors show that disorder-specific patterns of neuroanatomical changes are aligned to brain expression maps of disease risk genes in healthy subjects.

Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.

ObjectiveAs an active interface between the host and their diet, the gut bacteriome influences host metabolic adaptation. However, the contribution of gut fungi to host metabolic outcomes is not yet understood. Therefore, we aimed to determine if host metabolic response to an ultra-processed diet reflects gut fungal community composition.DesignWe compared jejunal fungi and bacteria from 72 healthy mice with the same genetic background but different starting mycobiomes before and after 8 weeks on an ultra-processed or standardized diet using 16S and internal transcribed spacer region 2 ribosomal RNA sequencing. We measured host body composition using magnetic resonance imaging, examined changes in metabolically active host tissues and quantified serum metabolic biomarkers.ResultsGut fungal communities are highly variable between mice, differing by vendor, age and sex. After exposure to an ultra-processed diet for 8 weeks, persistent differences in fungal community composition strongly associate with differential deposition of body mass in male mice compared to mice on standardized diet. Fat deposition in the liver, genomic adaptation of metabolically active tissues and serum metabolic biomarkers are correlated with alterations in fungal diversity and community composition. Variation in fungi from the genera Thermomyces and Saccharomyces most strongly associate with increased weight gain.ConclusionsIn the gut of healthy mice, host-microbe metabolic interactions strongly reflect variability in fungal communities. Our results confirm the importance of luminal fungal communities to host metabolic adaptation to dietary exposure. Gut fungal communities may represent a therapeutic target for the prevention and treatment of metabolic disease.Graphical AbstractIn BriefWhat is already known about this subject?Gut bacterial communities have evolved to influence the metabolic outcomes of the host in mammals. Evidence from across the lifespan suggests that differences in composition of these communities is associated with energy consumption. However, gut microbial communities, while often equated to bacteria, are diverse, multi-kingdom ecologies and limited information is available for the role of other kingdoms of life, such as fungi.What are the new findings?Gut fungal communities, collectively termed the mycobiome, are less diverse and abundant than bacterial communities in the gastrointestinal tract. This study identifies the considerable influence of the environment and dietary exposure on the composition of jejunal fungal communities in healthy mice with the same genetic background. After exposure to processed diet, differences in fungal community composition in male mice were strongly correlated with persistent differences body composition and markers of metabolic tone.How might it impact on clinical practice in the foreseeable future?These results verify that the baseline metabolic tone of health mice strongly reflects the ecological complexity of the gastrointestinal mycobiome. Variation in the composition of gut fungal communities is likely an underappreciated source of experimental and clinical variability in metabolic studies. Gastrointestinal fungi are likely a target for prevention and treatment of metabolic disease.

SummaryAlmost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.

In early childhood, individuals with Prader-Willi syndrome (PWS) experience excess weight gain and severe hyperphagia with food compulsivity, which often leads to early onset morbid obesity. Effective treatments for appetite suppression and weight control are currently unavailable for PWS. Our aim to further understand the pathogenesis of PWS led us to carry out a comprehensive search of the current and emerging therapies for managing hyperphagia and extreme weight gain in PWS. A literature search was performed using PubMed and the following keywords: "PWS" AND "therapy" OR "[drug name]"; reference lists, pharmaceutical websites, and the ClinicalTrials.gov registry were also reviewed. Articles presenting data from current standard treatments in PWS and also clinical trials of pharmacological agents in the pipeline were selected. Current standard treatments include dietary restriction/modifications, exercise, and growth hormone replacement, which appear to have limited efficacy for appetite and weight control in patients with PWS. The long-term safety and effectiveness of bariatric surgery in PWS remains unknown. However, many promising pharmacotherapies are in development and, if approved, will bring much needed choices into the PWS pharmacological armamentarium. With the progress that is currently being made in our understanding of PWS, an effective treatment may not be far off.

Background: Sex hormones play a role in gender identity development. For example, 46,XY individuals with complete androgen insensitivity typically have a female gender identity. Isolated GnRH deficiency (IGD) leads to hypogonadism due to decreased GnRH-induced gonadotropin production. It is unknown if decreased sex hormone exposure leads to differences in gender identity among individuals with IGD compared with the general population. Our objective was to determine if the gender identity in subjects with IGD differs from controls. Methods: We distributed a validated questionnaire; the Gender Identity/Gender Dysphoria Questionnaire for Adults and Adolescents (GIDYQ-AA) (1), to IGD participants who previously enrolled in a phenotyping study. Subjects also provided their age, sex assigned at birth (SAAB), gender and information about their condition and treatment. Group survey scores are expressed as mean ± SD. IGD subject scores were compared with control data (Student’s t-test) obtained from a validation study for the GIDYQ-AA (2). Results: Out of 79 subjects who were contacted, 8 males (M) assigned at birth and 7 females (F) assigned at birth chose to participate and one person actively declined. Average age was 30 y for F and 28 y for M. At the time of the study, all subjects were on hormone supplementation except for one F. A score of 5 indicates a gender identity congruent with SAAB. Among F, mean scaled IGD score was 4.73 ± 0.29 vs. controls (4.8 ± 0.28, n=57; not significant (ns)), and for M it was 4.62 ± 0.52 vs. controls (4.82 ± 0.24, n=37; ns). One female identified as “non-gendered”, one male identified as “intersex/DSD” (14% of respondents), one female did not respond and gender was congruent with SAAB in the remainder. The lowest mean score for an individual question for the IGD F group was in response to whether they felt satisfied being a woman and for the IGD M group, it was in response to whether they felt they were a real man. Conclusions: Men and women with IGD did not show a significant difference in their gender identity compared with controls, and gender was found to be congruent with SAAB for the majority. However, the individual question responses and the self-described gender in this small cohort may suggest that there are differences in how some individuals with IGD experience their gender development. We speculate that this may be related to how they perceive the differences in physical development that they experienced related to their condition. Larger studies in participants with IGD and other disorders that alter sex hormone production/effect are necessary to further understand the relationship between decreased sex hormone exposure during critical developmental periods and gender identity development. References: (1) Deogracias, J.J, et al. J. Sex Res., 2007, 44:4, 370–379 (2) Singh, D. et al. J. Sex Res. 2010, 47:1, 49–58

We investigated the associations between maternal dietary patterns during pregnancy and early childhood growth trajectories and overweight/obesity risk in offspring. Maternal diet was assessed using a food frequency questionnaire during the second trimester, and dietary patterns were derived by reduced rank regression. The associations between maternal dietary pattern scores and body mass index (BMI) trajectories from birth to age four (rising-high, moderate, and low BMI trajectories) as well as overweight/obesity risk at age four were analyzed (n = 1257). Two maternal dietary patterns were identified. The fast food pattern included a higher intake of fried chicken and fish, fruit juices, mayonnaise, and sugar-sweetened beverages, while the processed food pattern included a higher intake of dairy, salad dressing, processed meat, and cold breakfast cereal. Women with greater adherence to the fast food pattern were more likely to have children in the rising-high BMI trajectory group [OR (95% CI) = 1.32 (1.07&ndash, 1.62), p = 0.008] or having overweight/obesity at age four [OR (95% CI) = 1.31 (1.11&ndash, 1.54), p = 0.001]. The processed food pattern was not associated with these outcomes. The maternal dietary pattern during pregnancy represented by fried foods and sugar-sweetened beverages may contribute to rapid early childhood growth and increased risk for obesity in offspring.

Alström Syndrome is a ciliopathy associated with obesity, insulin resistance/type 2 diabetes mellitus, cardiomyopathy, retinal degeneration, hearing loss, progressive liver and kidney disease, and normal cognitive function. ALMS1, the protein defective in this disorder, localizes to the cytoskeleton, microtubule organizing center, as well as the centrosomes and ciliary basal bodies and plays roles in formation and maintenance of cilia, cell cycle regulation, and endosomal trafficking. Kidney disease in this disorder has not been well characterized. We performed comprehensive multisystem evaluations on 38 patients. Kidney function decreased progressively; eGFR varied inversely with age (p = 0.002). Eighteen percent met the definition for chronic kidney disease (eGFR < 60 mL/min/1.73 m(2) and proteinuria); all were adults with median age of 32.8 (20.6–37.9) years. After adjusting for age, there were no significant associations of kidney dysfunction with type 2 diabetes mellitus, dyslipidemia, hypertension, cardiomyopathy or portal hypertension suggesting that kidney disease in AS is a primary manifestation of the syndrome due to lack of ALMS1 protein. Approximately one-third of patients had hyperechogenicity of the renal parenchyma on imaging. While strict control of type 2 diabetes mellitus may decrease kidney-related morbidity and mortality in Alström syndrome, identification of novel targeted therapies is needed.

Children with cardiomyopathy are a vulnerable population and understanding the factors that contribute to cardiac dysfunction are of great importance. At the biochemical level, energy utilization by cardiomyocytes during stress may provide insight into the progression of cardiomyopathy. There is a large body of literature that describes insulin resistance in adults with cardiomyopathy (1,2). Extensive literature on the topic in adult individuals exists however investigation in the pediatric population is sparse. The pathophysiology of disease in children and adolescents is unique. To study the role of insulin resistance in pediatric cardiomyopathy, we measured the homeostasis model assessment-estimated insulin resistance (HOMA-IR) at baseline in pre-pubertal patients (age 13-18 years old; mean 16 years old; n = 8) with either hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). In patients with HCM, greater insulin resistance was positively correlated with greater left ventricular (LV) septal thickness (r = 0.55; p = 0.33; n = 5) and LV posterior wall thickness (r = 0.7; p = 0.19; n = 5) during diastole. As expected, insulin resistance was strongly correlated with BMI (r = 0.84; p = 0.08; n = 5) though greater BMI was not as strongly associated with LV septal thickness (r = 0.59; p = 0.3; n = 5) or posterior wall thickness (r = 0.59; p = 0.3; n = 5). In patients with DCM, insulin resistance was positively correlated with LV end diastolic volume (r = 0.59; p = 0.59; n = 3). Interestingly, there was an observed inverse association between insulin resistance and BMI in DCM (r = -0.85; p = 0.34; n =3). Though our sample population is limited, thus affecting statistical significance, results showed that there was a trend towards greater insulin resistance in patients with poorer cardiac measurements. These findings are consistent with adult literature and the proposition that cardiac dysfunction is an insulin resistant state. References: (1) Riehle C, Abel ED. Insulin Signaling and Heart Failure. Circulation research. 2016;118(7):1151-1169. (2) Shah A, Shannon RP. Insulin resistance in dilated cardiomyopathy. Reviews in cardiovascular medicine. 2003;4 Suppl 6:S50-57

The Healthy Lifestyle Clinic (HLC) is an interdisciplinary weight management clinic conceived to address alarming rates of pediatric obesity and related comorbidities in the midsouth region of the United States. The clinical cohort presented is a subset of the 609 patients evaluated during the first 2 years of the HLC and comprises 380 patients with a minimum of 6 months of follow-up. The primarily non-Hispanic black (67.1%) cohort presented with severe obesity ( MzBMI= 2.52 ± 0.41) and particularly high rates of insulin resistance, among other comorbidities. This article offers insight into the challenges of intervening with a cohort of youth and their families, many with limited resources to support intensive behavioral and lifestyle changes. Our experiences implementing a weight management clinic with a diverse clinical cohort provide guidance for emerging programs and impetus to investigate environmental and cultural factors that contribute to high attrition in the treatment of pediatric obesity.

Background The National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) has self-reported health measures available for both pediatric and adult populations, but no pediatric measures are available currently in the sleep domains. Objective The purpose of this observational study was to perform preliminary validation studies on age-appropriate, self-reported sleep measures in healthy adolescents. Methods This study examined 25 healthy adolescents’ self-reported daytime sleepiness, sleep disturbance, sleep-related impairment, and sleep patterns. Healthy adolescents completed a physical exam at the National Institutes of Health Clinical Center (Bethesda, MD), had no chronic medical conditions, and were not taking any chronic medications. The Cleveland Adolescent Sleepiness Questionnaire (CASQ), PROMIS Sleep Disturbance (v. 1.0; 8a), and PROMIS Sleep-Related Impairment (v. 1.0; 8b) questionnaires were completed, and sleep patterns were assessed using actigraphy. Results Total scores on the three sleep questionnaires were correlated (all Spearman’s r > .70, p < .001). Total sleep time determined by actigraphy was negatively correlated with the CASQ ( p = .01), PROMIS Sleep Disturbance ( p = .02), and PROMIS Sleep-Related Impairment ( p = .02). Discussion The field of pediatric sleep is rapidly expanding, and researchers and clinicians will benefit from well-designed, psychometrically sound sleep questionnaires. Findings suggest the potential research and clinical utility of adult versions of PROMIS sleep measures in adolescents. Future studies should include larger, more diverse samples and explore additional psychometric properties of PROMIS sleep measures to provide age-appropriate, validated, and reliable measures of sleep in adolescents.

Drug development and repurposing are urgently needed for individuals with autism spectrum disorders (ASD) and psychiatric comorbidity, which often presents as aggression and self-injury. Areas covered: We review dopamine antagonists, including classical and atypical, as well as unconventional antipsychotics in ASD. The older antipsychotic loxapine is discussed in terms of preliminary albeit limited evidence in ASD. Emerging promise of amitriptyline in ASD is discussed, together with promising BDNF effects of loxapine and amitriptyline. Expert opinion: In ASD, pharmacotherapy and specifically dopamine antagonist drugs are often prescribed for challenging behaviors including aggression. The novel antipsychotics risperidone and aripiprazole have received most study in ASD and are FDA-approved for irritability in children with ASD over age 5 years; individuals with ASD are prone to weight gain, Type II diabetes and associated side effects. Low dose loxapine has properties of classical and novel antipsychotics but importantly appears more weight neutral, and with promising use in adolescents and adults with ASD. Amitriptyline appears effective in ASD for irritability, aggression, gastrointestinal problems, and insomnia, in children, adolescents and adults however our adult data on amitriptyline in ASD is still in preparation for publication. Both loxapine and amitriptyline may stimulate BDNF; further studies are warranted.

The mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and age-associated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet-and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal muscle-specific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca2+ through SERCA2. Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan. These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.

Introduction Alströmsyndrome (AS) is an autosomal recessive ciliopathy caused by mutations inALMS1, which encodes a protein that localizes to centrosomes and basal bodies of primary cilia. Early emergence of obesity inpatients withAS suggests a key role for ALMS1 in body weight regulation. Mice with non-functional Alms1 develop normal hypothalamic cilia, but these are not maintained postnatally. This suggests involvement of the central pathways regulating energy balance in the development of obesity in AS. Since leptin signaling has been shown to be impaired in the related ciliopathy Bardet-Biedl syndrome, we hypothesized that targeting central pathways downstream of leptin signaling would reduce food intake and body weight inAlms1-/-mice. Methods Dose-response for the selective melanocortin 1/4 receptor agonist RM-493 (Setmelanotide) in suppressing food intake was determined in 19-wk-old femaleAlms1-/-mice(n=3) and wild-type (WT) littermates (n=3), individually housed and receiving daily intraperitoneal injections of vehicle (3 d) followed by RM-493 (3 d). A separate cohort of 17-wk-old male (n=4) and female (n=4)Alms1-/-mice had food intake measured continuously in metabolic cages(CLAMS, Columbus Instruments). After determining baseline food intake, mice received vehicle (2 d), followed by RM-493 (3 d), then 3d of washout (no treatment). Repeated measures ANOVA was performed. Mean ± SE and nominal p-values are shown. Results In the dose-response study,Alms-/-andWThadfood intake responses that weresimilarfor40(p=0.72),but differentfor100, 250, and 1000 nmol/kg/d (p’s0.84).RM-493(250 nmol/kg/d)reduced food intakein maleAlms1-/- compared to vehicle (-46.4%;p=0.003), causinganonsignificantreduction in body weight(-13.1%;p=0.33),whereasfood intakein femaleAlms1-/-wasreduced by 28.5%,and body weight by 6.5%,althoughneither difference was significant (p’s>0.61).During the washout period, maleAlms1-/-ate 62.8% more food than during the vehicle period(p

Neurodevelopmental disorders are highly heritable and associated with spatially-selective disruptions of brain anatomy. The logic that translates genetic risks into spatially patterned brain vulnerabilities remains unclear but is a fundamental question in disease pathogenesis. Here, we approach this question by integrating (i)in vivoneuroimaging data from patient subgroups with known causal genomic copy number variations (CNVs), and (ii) bulk and single-cell gene expression data from healthy cortex. First, for each of six different CNV disorders, we show that spatial patterns of cortical anatomy change in youth are correlated with spatial patterns of expression for CNV region genes in bulk cortical tissue from typically-developing adults. Next, by transforming normative bulk-tissue cortical expression data into cell-type expression maps, we further link each disorder’s anatomical change map to specific cell classes and specific CNV-region genes that these cells express. Finally, we establish convergent validity of this “transcriptional vulnerability model” by inter-relating patient neuroimaging data with measures of altered gene expression in both brain and blood-derived patient tissue. Our work clarifies general biological principles that govern the mapping of genetic risks onto regional brain disruption in neurodevelopmental disorders. We present new methods that can harness these principles to screen for potential cellular and molecular determinants of disease from readily available patient neuroimaging data.

It is well documented that influenza A viruses selectively package 8 distinct viral ribonucleoprotein complexes (vRNPs) into each virion; however, the role of host factors in genome assembly is not completely understood. To evaluate the significance of cellular factors in genome assembly, we generated a reporter virus carrying a tetracysteine tag in the NP gene (NP-Tc virus) and assessed the dynamics of vRNP localization with cellular components by fluorescence microscopy. At early time points, vRNP complexes were preferentially exported to the MTOC; subsequently, vRNPs associated on vesicles positive for cellular factor Rab11a and formed distinct vRNP bundles that trafficked to the plasma membrane on microtubule networks. In Rab11a deficient cells, however, vRNP bundles were smaller in the cytoplasm with less co-localization between different vRNP segments. Furthermore, Rab11a deficiency increased the production of non-infectious particles with higher RNA copy number to PFU ratios, indicative of defects in specific genome assembly. These results indicate that Rab11a+ vesicles serve as hubs for the congregation of vRNP complexes and enable specific genome assembly through vRNP:vRNP interactions, revealing the importance of Rab11a as a critical host factor for influenza A virus genome assembly., Author summary The influenza A virus (IAV) genome is composed of 8 distinct RNA segments. It has remained unclear how these 8 individual RNA segments are assembled together to form infectious virus particles. Our study shows that Rab11a+ vesicles serve as platforms for the congregation and assembly of 8 individual viral RNA segments needed to form infectious virus particles. However, in cells lacking Rab11a, viral RNA segments fail to congregate together, resulting in increased production of defective virus particles, likely due to misassembling of viral RNA segments. Thus, our study reveals the important role for Rab11a in influenza virus genome assembly and production of infectious virus particles.

Introduction: This randomized Phase 3 trial evaluated the effect of setmelanotide, a melanocortin 4 receptor agonist, on weight loss, hunger reduction, and safety outcomes in individuals (aged ≥6 years) with obesity and a genetically confirmed diagnosis of Bardet-Biedl syndrome (BBS) or Alström syndrome (AS), conditions believed to disrupt hypothalamic leptin-melanocortin signaling. Methods: For inclusion, obesity was defined as body mass index ≥30 kg/m2 (in those aged ≥16 years) or weight >97th percentile (in those aged 6–15 years). Individuals were randomized and received setmelanotide or placebo for 14 weeks, followed by open-label setmelanotide so that all participants received at least 1 year of drug. Body weight, height, hunger scores, and treatment-emergent adverse events (AEs) were assessed. The primary endpoint was the proportion of participants (≥12 years) who achieved ≥10% reduction in body weight from baseline after 52 weeks of treatment. For statistical analysis, the primary endpoint had binomial proportions calculated for each of the 100 multiple imputed data sets, which were combined using Rubin’s Rule to compare against the null hypothesis with 95% confidence intervals (CIs) and P values. Efficacy analyses (including change in body weight, body mass index Z score, and hunger) were conducted in participants ≥12 years old at baseline. Safety analyses were conducted in all participants. Results: A total of 38 individuals with BBS (n=32) or AS (n=6) were enrolled. Five participants