Evaluation of Autonomic Nervous System Dysfunction in Childhood Obesity and Prader-Willi Syndrome.

The autonomic nervous system (ANS) may play a role in the distribution of body fat and the development of obesity and its complications. Features of individuals with Prader-Willi syndrome (PWS) impacted by PWS molecular genetic classes suggest alterations in ANS function; however, these have been rarely studied and presented with conflicting results. The aim of this study was to investigate if the ANS function is altered in PWS. In this case-control study, we assessed ANS function in 20 subjects with PWS (6 males/14 females; median age 10.5 years) and 27 body mass index (BMI) z-score-matched controls (19 males/8 females; median age 12.8 years). Standardized non-invasive measures of cardiac baroreflex function, heart rate, blood pressure, heart rate variability, quantitative sudomotor axon reflex tests, and a symptom questionnaire were completed. The increase in heart rate in response to head-up tilt testing was blunted (p < 0.01) in PWS compared to controls. Besides a lower heart rate ratio with Valsalva in PWS (p < 0.01), no significant differences were observed in other measures of cardiac function or sweat production. Findings suggest possible altered sympathetic function in PWS.

Preserved Sleep for the Same Level of Respiratory Disturbance in Children with Prader-Willi Syndrome.

Debate remains as to how to balance the use of recombinant human growth hormone (rhGH) as an important treatment in Prader-Willi syndrome (PWS) with its potential role in obstructive sleep apnea. This single-center, retrospective study assessed differences in overnight polysomnography results between children with and without PWS and changes in respiratory parameters before and after the initiation of rhGH treatment in those with PWS. Compared with age-, sex-, and body-mass-index-matched controls (n = 87), children with PWS (n = 29) had longer total sleep time (434 ± 72 vs. 365 ± 116 min; p < 0.01), higher sleep efficiency (86 ± 7 vs. 78 ± 15%; p < 0.05), and lower arousal events (8.1 ± 4.5 vs. 13.0 ± 8.9 events/h; p < 0.05). Mean oxygen saturation was lower in PWS children (94.3 ± 6.0 vs. 96.0 ± 2.0%; p < 0.05), with no other differences in respiratory parameters between groups. Eleven children with PWS (38%) met the criteria for further analyses of the impact of rhGH; polysomnography parameters did not change with treatment. Compared with other children undergoing polysomnography, children with PWS had more favorable markers of sleep continuity and lower oxygen saturation for the same level of respiratory disturbance. rhGH administration was not associated with changes in respiratory parameters in PWS.

Recent Advances in Incretin-Based Pharmacotherapies for the Treatment of Obesity and Diabetes.

The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2-3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies.

Composition and Functions of the Gut Microbiome in Pediatric Obesity: Relationships with Markers of Insulin Resistance.

The gut microbiome is hypothesized to play a crucial role in the development of obesity and insulin resistance (IR); the pathways linking the microbiome to IR in pediatrics have yet to be precisely characterized. We aimed to determine the relationship between the gut microbiome composition and metabolic functions and IR in children with obesity. In a cross-sectional study, fecal samples from children with obesity (10-16 years old) were collected for taxonomical and functional analysis of the fecal microbiome using shotgun metagenomics. The homeostatic model assessment for insulin resistance (HOMA-IR) was determined using fasting glucose and insulin. Associations between HOMA-IR and α-diversity measures as well as metabolic pathways were evaluated using Spearman correlations; relationships between HOMA-IR and ß-diversity were assessed by permutational multivariate analysis of variance. Twenty-one children (nine males; median: age = 12.0 years; BMI z-score = 2.9; HOMA-IR = 3.6) completed the study. HOMA-IR was significantly associated with measures of α-diversity but not with ß-diversity. Children with higher HOMA-IR exhibited lower overall species richness, Firmicutes species richness, and overall Proteobacteria species Shannon diversity. Furthermore, HOMA-IR was inversely correlated with the abundance of pathways related to the biosynthesis of lipopolysaccharides, amino acids, and short-chain fatty acids, whereas positive correlations between HOMA-IR and the peptidoglycan biosynthesis pathways were observed. In conclusion, insulin resistance was associated with decreased microbial α-diversity measures and abundance of genes related to the metabolic pathways. Our study provides a framework for understanding the microbial alterations in pediatric obesity.

Probiotics, prebiotics, synbiotics, and fecal microbiota transplantation in the treatment of behavioral symptoms of autism spectrum disorder: A systematic review.

The emerging role of a microbiota-gut-brain axis in autism spectrum disorder (ASD) suggests that modulating gut microbial composition may offer a tractable approach to addressing the lifelong challenges of ASD. The aim of this systematic review was to provide an overview and critically evaluate the current evidence on the efficacy and safety of probiotic, prebiotic, synbiotic, and fecal microbiota transplantation therapies for core and co-occurring behavioral symptoms in individuals with ASD. Comprehensive searches of MEDLINE, EMBASE, Scopus, Web of Science Core Collection, Cochrane Library, and Google Scholar were performed from inception to March 5, 2020, and two update searches were completed on October 25, 2020, and April 22, 2021, respectively. A total of 4306 publications were identified, of which 14 articles met the inclusion criteria. Data were extracted independently by two reviewers using a preconstructed form. Results of probiotic studies do not confirm the supposed beneficial effect of probiotics on ASD, whereas prebiotics and synbiotic combinations appear to be efficacious in selective behavioral symptoms. Evidence of the efficacy of fecal microbiota transplantation in ASD is still scarce but supports further research. Overall, the current evidence base to suggest beneficial effects of these modalities in ASD is limited and inconclusive. More clinical trials are currently looking at the use of microbial-based therapies in ASD. With a robust double-blind randomized controlled protocol to investigate the efficacy, these trials should provide significant and definitive results. LAY SUMMARY: There is a link between altered gut bacteria and autism spectrum disorder. Some people believe that modulating bacterial composition in the gut may help reduce autism symptoms, but evidence from human studies suggesting beneficial effects of probiotic, prebiotic, and combination thereof as well as fecal transplants in autism spectrum disorder is limited and inconclusive. Current data should not encourage use of these modalities. Further clinical studies are needed.

Complexity and Stigma of Pediatric Obesity.

Weight stigma is rooted in a fundamental misunderstanding of the origins of obesity, wherein the interplay of behavioral, environmental, genetic, and metabolic factors is deemphasized. Instead, the widespread societal and cultural presence of weight stigma fosters misconceptions of obesity being solely a result of unhealthy personal choices. Weight stigma is pervasive in childhood and adolescence and can affect individuals throughout their life. Although the prevalence of pediatric obesity remains high throughout the world, it becomes increasingly important to understand how weight stigma affects weight and health outcomes in children and adolescents with overweight or obesity, including in those with rare genetic diseases of obesity. We identified and reviewed recent literature (primarily published since 2000) on weight stigma in the pediatric setting. Articles were identified with search terms including pediatric obesity, weight bias, weight stigma, weight-based teasing and bullying, and weight bias in health care. In this narrative review, we discuss the stigma of pediatric obesity as it relates to the complex etiology of obesity as well as describe best practices for avoiding bias and perpetuating stigma in the health care setting.

Efficacy of metformin and fermentable fiber combination therapy in adolescents with severe obesity and insulin resistance: study protocol for a double-blind randomized controlled trial.

BACKGROUND: Accumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal models have established that the addition of fiber to metformin monotherapy improves glucose tolerance. However, possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. Moreover, the underlying mechanisms of synergy have yet to be elucidated. The aim of this study is to compare in adolescents with obesity the metabolic effects of metformin and fermentable fibers in combination with those of metformin or fiber alone. We will also determine if therapeutic responses correlate with compositional and functional features of the gut microbiome. METHODS: This is a parallel three-armed, double-blinded, randomized controlled trial. Adolescents (aged 12-18 years) with obesity, insulin resistance (IR), and a family history of type 2 diabetes mellitus (T2DM) will receive either metformin (850 mg p.o. twice/day), fermentable fibers (35 g/day), or a combination of metformin plus fiber for 12 months. Participants will be seen at baseline, 3, 6, and 12 months, with a phone follow-up at 1 and 9 months. Primary and secondary outcomes will be assessed at baseline, 6, and 12 months. The primary outcome is change in IR estimated by homeostatic model assessment of IR; key secondary outcomes include changes in the Matsuda index, oral disposition index, body mass index z-score, and fat mass to fat-free mass ratio. To gain mechanistic insight, endpoints that reflect host-microbiota interactions will also be assessed: obesity-related immune, metabolic, and satiety markers; humoral metabolites; and fecal microbiota composition, short-chain fatty acids, and bile acids. DISCUSSION: This study will compare the potential metabolic benefits of fiber with those of metformin in adolescents with obesity, determine if metformin and fiber act synergistically to improve IR, and elucidate whether the metabolic benefits of metformin and fiber associate with changes in fecal microbiota composition and the output of health-related metabolites. This study will provide insight into the potential role of the gut microbiome as a target for enhancing the therapeutic efficacy of emerging treatments for T2DM prevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04578652 . Registered on 8 October 2020.

The Gut Microbiota Profile in Children with Prader-Willi Syndrome.

Although gut microbiota has been suggested to play a role in disease phenotypes of Prader-Willi syndrome (PWS), little is known about its composition in affected children and how it relates to hyperphagia. This cross-sectional study aimed to characterize the gut bacterial and fungal communities of children with PWS, and to determine associations with hyperphagia. Fecal samples were collected from 25 children with PWS and 25 age-, sex-, and body mass index-matched controls. Dietary intake data, hyperphagia scores, and relevant clinical information were also obtained. Fecal bacterial and fungal communities were characterized by 16S rRNA and ITS2 sequencing, respectively. Overall bacterial α-diversity and compositions of PWS were not different from those of the controls, but 13 bacterial genera were identified to be differentially abundant. Interestingly, the fungal community, as well as specific genera, were different between PWS and controls. The majority of the variation in the gut microbiota was not attributed to differences in dietary intake or the impact of genotype. Hyperphagia scores were associated with fungal α-diversity and relative abundance of several taxa, such as Staphylococcus, Clostridium, SMB53, and Candida. Further longitudinal studies correlating changes in the microbiome with the degree of hyperphagia and studies integrating multi-omics data are warranted.

Prader-Willi-Like Phenotype Caused by an Atypical 15q11.2 Microdeletion.

We report a 17-year-old boy who met most of the major Prader-Willi syndrome (PWS) diagnostic criteria, including infantile hypotonia and poor feeding followed by hyperphagia, early-onset morbid obesity, delayed development, and characteristic facial features. However, unlike many children with PWS, he had spontaneous onset of puberty and reached a tall adult stature without growth hormone replacement therapy. A phenotype-driven genetic analysis using exome sequencing identified a heterozygous microdeletion of 71 kb in size at chr15:25,296,613-25,367,633, genome build hg 19. This deletion does not affect the SNURF-SNRPN locus, but results in the loss of several of the PWS-associated non-coding RNA species, including the SNORD116 cluster. We compared with six previous reports of patients with PWS who carried small atypical deletions encompassing the snoRNA SNORD116 cluster. These patients share similar core symptoms of PWS while displaying some atypical features, suggesting that other genes in the region may make lesser phenotypic contributions. Altogether, these rare cases provide convincing evidence that loss of the paternal copy of the SNORD116 snoRNA is sufficient to cause most of the major clinical features of PWS.

Current and emerging therapies for managing hyperphagia and obesity in Prader-Willi syndrome: A narrative review.

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.

Epidemiological survey of Angiostrongylus cantonensis in the west-central region of Guangdong Province, China.

The study was to understand the Angiostrongylus cantonensis infectious situation of rodent definitive host, snail intermediate host, and local residents in the west-central region of Guangdong Province in China. The snails Achatina fulica and Pomacea canaliculata collected from the survey place were digested with artificial gastric juice, and the third-stage larvae of A. cantonensis in the snails were examined under microscope. The heart and lung of rats captured from the survey place were taken to check the adult of A. cantonensis. The questionnaire surveys related to the infection of A. cantonensis were taken in local residents randomly selected, and the IgG antibody against A. cantonensis was tested in those residents with enzyme-linked immunosorbent assay (ELISA). A total of 1,391 rats including eight kinds of rats, such as Rattus norvegicus, Rattus flavipectus, Bandicota indica, Rattus sladeni, Mus musculus, Rattus rattoides, Suncus Murinus, and Rattus confucianus, were examined and 132 of them were infected by A. cantonensis, with an average infection rate of 9.49% and a mean intensity of A. cantonensis in infected rats was 9.39. A total of 3,184 snails A. fulica and 3,723 snails P. canaliculata were detected. The average infection rates of them were 25.03% (797/3,184) and 6.50% (242/3,723), respectively. There were 180 positive samples of IgG antibody against A. cantonensis in 1,800 serum samples of the residents, with a positive rate of 10.00%. The west-central region of Guangdong Province is the natural focus of A. cantonensis. In comparison with the investigation results in other regions of China, the infection rate of rat definitive host is at the middle level; in the intermediate host, the infection rate of snail A. fulica is above the middle level, and the infection rate of snail Pomacea canaliculata is below the middle level. Some local residents had already been infected by A. cantonensis or at the risk of being infected.

[Epidemiological investigation of Angiostrongylus cantonensis in Jiangmen of Guangdong Province].

OBJECTIVE: To make an epidemiological survey on Angiostrongylus cantonensis in Jiangmen City of Guangdong Province. METHODS: From October 2006 to November 2007, the characteristics of A. cantonensis infection were investigated in Jiangmen district in various hosts, including the third stage larva infection in the snails Achatina fulica and Pomacea canaliculata by digestion method, and the adult A. cantonensis in rats by the dissection of heart and lungs. Relevant symptoms and dietary habits in Jiangmen residents who were randomly recruited were also investigated by questionnaire, and the specific IgG and IgM antibodies against A. cantonensis in their sera were detected by ELISA. RESULTS: 695 A. fulica and 720 P. canaliculata were examined. The infection rate of third stage larva of A. cantonensis were 45.0% and 1.8% respectively, with an infectivity of 53.74+/-147.30 and 5.23+/-8.51 respectively. Natural infection rate of A. cantonensis in all 229 rats was 4.4%. Among the 300 people surveyed, 11.3% had a history of eating raw or undercooked fish and shrimp, 5.3% directly or indirectly exposed to A. fulica or P. canaliculata. The positive rate of specific IgG antibody against A. cantonensis for serum samples among residents was 14.0% (42/300), and 5 serum samples in the 42 positive samples showed specific IgM antibody, with a positive rate of 1.7%. CONCLUSION: Jiangmen district is an endemic area of A. cantonensis, and the local residents are under the risk of infection.