Mechanisms of Obesity and Its Metabolic Complications in Youth

Study Overview
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Brief Summary
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The overarching goal of this project is to determine whether the effect of gut microbiota on human metabolism might be mediated by short chain fatty acids (SCFA) and whether the SCFA might modulate lipid metabolism.

Detailed Description
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This would be the first study determining the effect of SCFA synthesis on hepatic de novo lipogenesis and to assess whether and how isocaloric dietary changes (namely low carbohydrates) might modify the composition of the gut microbiota and reduce the synthesis of SCFA during adolescence, a sensitive period for the development of obesity.

Official Title
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Mechanisms of Obesity and Its Metabolic Complications in Youth

Conditions
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Obesity, Childhood

Intervention / Treatment
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* Dietary Supplement: obese carbohydrate diet
* Dietary Supplement: lean carbohydrate diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Good general health, Taking no medication on a chronic basis Age 15 to 21 years, In puberty (girls and boys: Tanner stage III - V) BMI >25th and <85th for lean cohort; BMI >95th for obese cohort Girls who begin menstruating must have a negative pregnancy test during the study. Exclusion criteria: Baseline creatinine >1.0 mg Food allergies Pregnancy Presence of endocrinopathies (e.g. Cushing syndrome) Significant chronic illness.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: obese carbohydrate diet<br>Obese adolescents with a body mass index (BMI) >95th percentile. | Dietary Supplement: obese carbohydrate diet<br>* The experimental diet will consist of 30% carbohydrates (CHO), 35% protein, and 35% fat. Since the experimental diet is lower in CHO, the fiber and sugar content will be calculated based on total CHO in the same percentage as the control (0.25 g fiber per each kcal of CHO and 18.2% sugar for total CHO).<br>|
| Active Comparator: lean carbohydrate diet<br>Lean adolescents with a body mass index (BMI) <85th percentile. | Dietary Supplement: lean carbohydrate diet<br>* The control diet composition will follow the American Dietary Guidelines of 55% carbohydrates (CHO), 15% protein, and 30% fat. CHO content will be primarily complex CHO of high quality (14 g fiber/1,000 kcals and <10% of total kcals in the form of sugar).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For an equal amount of dietary carbohydrates, obese youth will synthesize short chain fatty acids at higher rates than lean youth. | Subjects will be given orally 15g of deuterated inulin every 30 minutes.Total acetate is calculated by summing the synthetic rates of the single acetate. The primary outcome will be the peak percent change from fasting in total acetate estimated by dividing the difference between total acetate at fasting and the peak total acetate by the total acetate at fasting. | 4 hours | 
| If high rates of short chain fatty acid (SCFA) synthesis enhance hepatic de novo lipogenesis. | Subjects will consume 2g of Inulin, 13g of unlabeled inulin. Blood draws will be taken every hour. To evaluate the association between total SCFA and de novo lipogenesis, peak percent changes in de novo lipogenesis will be regressed on peak percent changes in total SCFA. | 12 hours | 
| The effect of an isocaloric low carbohydrate (CHO) diet on the bacterial synthesis of short chain fatty acids (SCFA). | Subjects will be enrolled in a low carbohydrate diet. The percent change in peak total acetate rate, calculated as the follow-up peak total acetate minus the baseline peak total acetate divided by the baseline peak total acetate, will be compared between the low CHO period and the control period. | 1 week |