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.

A two-component pictured-based appetite assessment tool is capable of detecting appetite sensations in younger children: A pilot study.

Visual analogue scales (VAS) have commonly been used to assess appetite in children 8 years and older; however, these tools have been considered unreliable for children 7 years old and under. The objective of this pilot study was to develop a picture-based appetite assessment (PBAA) tool for children aged 4-10 years and pilot test it compared to a VAS-based appetite assessment. The study hypothesis was that the PBAA scores would decrease following the consumption of an ad libitum snack compared to the scores in the fasted state in children 4 to 10 years old; furthermore, there would be a good level of agreement (intraclass correlation coefficients >0.75) between the appetite scores by the PBAA and VAS tools in children aged 8 years or older. At Visit 1, in a fasted state, all children (n = 15) completed the PBAA. Children who were 8-10 years old (n = 8) also completed the VAS-based appetite assessment. Then, an ad libitum snack was provided, and appetite assessments were repeated at 5-, 30- and 60-minutes post-snack. The same assessments were completed at visit 2 pre (fasting)- and post-consumption of a snack containing 25% of the amount consumed at visit 1 (limited snack). PBAA scores were different across time (P < .001) and between types of meal (ad libitum vs limited snack) (P = .015) in all children. A good agreement between the PBAA and VAS scores at 30 and 60 minutes after both types of meal was found (intraclass correlation coefficients >0.75). The PBAA tool was able to detect expected changes in appetite sensations and was in good agreement with the VAS instrument.

Effect of High-Protein Diet on Postprandial Energy Expenditure in Children with Prader-Willi Syndrome: A Pilot and Feasibility Study.

The aim of this study was to explore the feasibility of measuring a postprandial increase in energy expenditure (ΔEE) using a state-of-the-art whole-body calorimetry unit (WBCU) in children and youth with Prader-Willi syndrome (PWS). Five participants (aged 10-25 y) received both a standard and a high-protein diet in a random order (crossover design). Resting energy expenditure, postprandial ΔEE 6 h after intake of a standard [15% of total energy (TE)] and a high-protein (30% TE) meal, and respiratory exchange ratio (RER) were measured in a WBCU. No differences were observed in ΔEE comparing the 2 meals. Mean RER was lower following the high-protein meal (0.80 ± 0.01) compared with the standard meal (0.87 ± 0.02) (P = 0.009). Despite the high participant burden, it was feasible to conduct this metabolic test in children and youth with PWS. This study paves the way for further studies targeting EE in this patient population.

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.

Precision Microbiome Modulation with Discrete Dietary Fiber Structures Directs Short-Chain Fatty Acid Production.

Dietary fibers (DFs) impact the gut microbiome in ways often considered beneficial. However, it is unknown if precise and predictable manipulations of the gut microbiota, and especially its metabolic activity, can be achieved through DFs with discrete chemical structures. Using a dose-response trial with three type-IV resistant starches (RS4s) in healthy humans, we found that crystalline and phosphate cross-linked starch structures induce divergent and highly specific effects on microbiome composition that are linked to directed shifts in the output of either propionate or butyrate. The dominant RS4-induced effects were remarkably consistent within treatment groups, dose-dependent plateauing at 35 g/day, and can be explained by substrate-specific binding and utilization of the RS4s by bacterial taxa with different pathways for starch metabolism. Overall, these findings support the potential of using discrete DF structures to achieve targeted manipulations of the gut microbiome and its metabolic functions relevant to health.

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.

Hormonal and metabolic effects of carbohydrate restriction in children with Prader-Willi syndrome.

OBJECTIVE: Macronutrient regulation of hyperphagia and adiposity in Prader-Willi syndrome (PWS) is poorly understood. We compared fasting and postprandial concentrations of hormones and metabolites in eight PWS children (age 9-18 years) fed, in random order, low carbohydrate, high-fat (LC, 15% carb; 65% fat; 20% protein) and low-fat, high carbohydrate (LF, 65% carb, 15% fat, 20% protein) diets matched for calories and protein. METHODS: Participants were randomized to consume either the LC or LF diet during a first hospital admission and the second diet during a subsequent admission. Blood samples were obtained after overnight fasting and 1 hour after a mixed meal. RESULTS: Relative to subjects consuming the LF diet, subjects consuming the LC diet had: lower postprandial insulin concentrations (P = 0.02); higher fasting GLP-1 AND GIP concentrations and increased postprandial GLP-1 (P < 0.02); reduced ratio of fasting ghrelin to GLP-1 (P = 0.0078); increased FFA and fatty acid oxidation, as assessed by concentrations of even-chain acylcarnitines (P < 0.001); lower fasting TG and TG/HDL ratio (P < 0.01); and higher concentrations of branch chain amino acids (P < 0.01). There were no changes in glucose, PYY, or adiponectin. CRP, AST and ALT were all higher (P < 0.01) on the LC diet. CONCLUSIONS: Increases in GLP-1 with low carbohydrate feeding and reductions in the ratio of ghrelin to GLP-1 might limit food intake and improve glycaemic control in PWS. Other potential benefits of carbohydrate restriction may include fat mobilization and oxidation and reductions in the TG/HDL ratio, a marker of insulin resistance. However, increases in CRP, AST and ALT necessitate longer-term studies of low carbohydrate efficacy and safety.

Dietary intake in youth with prader-willi syndrome.

Dietary management is important to prevent severe obesity in individuals with Prader-Willi syndrome (PWS); however, few studies have examined dietary intake and quality in youth with PWS. Our objective was to estimate intake of essential nutrients and diet quality in youth with PWS compared to those without PWS. Three-day food records were used to estimate intake of energy, nutrients, nutrient-density, foods, and adherence to healthy eating guidelines. Data were presented as medians and interquartile ranges with Mann-Whitney U and Fisher's test used to compare between groups with p < .05 considered significant. Youth with (n = 23) and without (n = 23) PWS were similar in age and sex distribution. The PWS group had a lower energy intake (p ≤ .001), higher nutrient density (p = .003), and better adherence to guidelines (p = .007) compared to the control group. The proportion with nutrient intake from food below Estimated Average Requirement or Adequate Intake were similar between groups. Fiber, vitamin D, calcium, and potassium intake were below recommendations in 50% or more in both groups. The inclusion of supplement intake lowered the proportion below recommendations, except for fiber and potassium. Youth with PWS had a similar nutrient intake as those without PWS despite a lower energy intake, which could be attributed to higher diet quality. However, more than half of youth with PWS were at risk of inadequate fiber, vitamin D, calcium, and potassium intake. A greater emphasis on nutrient-dense foods would improve nutrient intake, but supplements may be warranted in youth with PWS who do not meet recommendations.

The Impact of School Gardening on Cree Children's Knowledge and Attitudes toward Vegetables and Fruit.

PURPOSE: School-based interventions may increase children's preferences for vegetables and fruit (V&F). This Canadian study measured changes in Indigenous First Nations schoolchildren's V&F knowledge, preferences, and home consumption following the implementation of a gardening and V&F snack program. METHODS: At baseline, 7 months, and 18 months, children in grades 1-6 (i) listed at least 5 V&F they knew, (ii) tasted and indicated their preferences towards 9 vegetables and 8 fruit using a 6-point Likert scale, and (iii) indicated their home consumption of 17 V&F. RESULTS: At all 3 time points, 56.8% (n = 66/116) of children provided data. Children listed a greater number of V&F at 18 months (4.9 ± 0.1) than at baseline (4.5 ± 1.0) or 7 months (4.7 ± .07) (F(1.6,105.6) = 6.225, P < 0.05). Vegetable preferences became more positive between baseline (37.9 ± 9.3) and 7 months (39.9 ± 9.2), but returned to baseline levels at 18 months (37.3 ± 8.7) (F(1.6,105.8) = 4.581, P < 0.05). Fruit preferences at 18 months (42.7 ± 3.0) were greater than at baseline (41.1 ± 4.3) and at 7 months (41.9 ± 5.1) (F(1.7,113.3) = 3.409, P < 0.05). No change in V&F consumption occurred at home. CONCLUSIONS: Despite improvements in V&F knowledge and preferences, home consumption of V&F did not occur. Complementing school-based programs with home-based components may be needed to influence V&F intake of children.

A school gardening and healthy snack program increased Aboriginal First Nations children's preferences toward vegetables and fruit.

OBJECTIVE: The researchers evaluated the impact of a 7-month gardening and 4-month vegetable and fruit snack program on Aboriginal First Nations children's home consumption and preferences toward vegetables and fruit. METHODS: The intervention was based on the Social Cognitive Theory. Children in grades 1-6 planted and tended classroom container gardens and prepared and ate what grew. At baseline and 7 months later, children tasted and rated 17 vegetables and fruit using a Likert scale and indicated whether they ate each food at home. RESULTS: Data were collected from 76 of 116 children (65.5%). Preference scores for vegetables, fruit, and vegetables and fruit combined increased over the 7 months (P < .017). Self-reported home consumption did not change. CONCLUSIONS AND IMPLICATIONS: School interventions have the potential to increase children's preferences for vegetables and fruit. Family participation is likely required, along with increased community availability of produce, to promote home consumption.