FB4 (Framingham, Boston, Bloomington, Birmingham, and Baylor)

Study Overview
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Brief Summary
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This study will evaluate the effects of dietary carbohydrate and sugar consumption, independent of energy content, on body fatness and metabolism in a rigorous feeding study.

Detailed Description
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Many people with obesity can lose weight for a few months, but most have difficulty maintaining weight loss over the long term. Extensive research has shown that weight loss elicits biological adaptations - including a decline in energy expenditure and an increase in hunger - that promote weight regain. However, this observation leaves unanswered why average body weight has recently increased among populations that are mostly genetically stable. According to the Carbohydrate-Insulin Model, increased consumption of processed carbohydrates during the low-fat diet era of the last 40 years has raised the average body weight being defended by biological mechanisms on a population basis. Specifically, the investigators hypothesize that diets high in total carbohydrate (with or without added sugar) acting through increased insulin secretion, alter substrate partitioning toward storage in body fat, leading to increased hunger, slowing metabolism, and accumulation of body fat. To test this hypothesis, the investigators plan a randomized-controlled feeding study involving 125 adults with obesity. During the run-in phase, participants will be given a hypocaloric very-low-carbohydrate (VLC) diet, with adjustment of energy intake to produce 15 ± 3% weight loss over 3 to 4 months on an outpatient basis. After weight stabilization, participants will be admitted to a residential center for 13 weeks. During the first 3 weeks, energy intake and expenditure will be closely monitored during weight-loss maintenance. Then, energy intake will be individually locked at levels equal to energy expenditure and participants will be administered one of three randomly-assigned test diets for 10 weeks. The test diets include VLC, High Carbohydrate-Low Sugar (HC-LS), and High Carbohydrate-High Sugar (HC-HS).

Official Title
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Macronutrients and Body Fat Accumulation: A Mechanistic Feeding Study

Conditions
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Obesity

Intervention / Treatment
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* Behavioral: Feeding Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 to 50 years BMI ≥ 27 kg/m2 Weight ≤ 350 lb Medical clearance from a primary care provider Willingness to follow a VLC weight-loss diet Willingness to reside in a research unit for 3 months and eat/drink only provided study foods and beverages No major food allergies or aversions Willingness to obtain seasonal flu shot or provide documentation of flu shot for current flu season (winter/spring cohort only) Willingness to discuss work options (e.g., remote work) with employer, and make appropriate arrangements prior to the Residential phase. Exclusion Criteria: Change in body weight ≥ 10% during prior 6 months Specialized diets (e.g., for medical or religious reasons) Chronic use of any medication or dietary supplement that could affect study outcomes (e.g., insulin, metformin, thyroxine) Current smoking (1 cigarette in the last week) Greater than moderate alcohol consumption (> 14 drinks/wk) or history of binge drinking (≥5 drinks in 1 day within past 6 months) Physician diagnosis of a major medical illness or eating disorder History of kidney stones Laboratory tests: ALT>2x upper limit; abnormal HgA1c; abnormal TSH; abnormal creatinine; abnormal uric acid (using the male upper limit for both sexes) Failed criminal offender background check or sex offender background check Use of recreational drugs Current diagnosis or history of kidney stones, gout, or gall stones; or removal of gall bladder Exercise restrictions or at high risk for complications during exercise Female-specific exclusion criteria: Menopausal Any change in birth control medication during the 3 months prior to enrollment Pregnancy or lactation during the 12 months prior to enrollment, or intent to become pregnant during study participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Very-Low Carbohydrate Diet<br>Feeding study. Dietary composition (approximately): 75% fat | Behavioral: Feeding Study<br>* Food provision throughout the study: 1) Run-In Phase (VLC diet, weight loss); 2) Residential Phase (3 different test diets, weight-loss maintenance).<br>* Other names: weight loss, weight-loss maintenance;|
| Experimental: High-Carbohydrate Low-Sugar Diet<br>Feeding study. Dietary composition (approximately): 25% fat 0% added sugars. | Behavioral: Feeding Study<br>* Food provision throughout the study: 1) Run-In Phase (VLC diet, weight loss); 2) Residential Phase (3 different test diets, weight-loss maintenance).<br>* Other names: weight loss, weight-loss maintenance;|
| Experimental: High-Carbohydrate High-Sugar Diet<br>Feeding study. Dietary composition (approximately): 25% fat, 20% added sugars. | Behavioral: Feeding Study<br>* Food provision throughout the study: 1) Run-In Phase (VLC diet, weight loss); 2) Residential Phase (3 different test diets, weight-loss maintenance).<br>* Other names: weight loss, weight-loss maintenance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body fat mass | Body composition assessed using a multi-component model | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lean body mass | Assessed using a multi-component model (difference between total body mass and fat mass) | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Body weight | Anthropometrics, assessed by calibrated scale, in kilograms (kg) | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Total energy expenditure (TEE) | Assessed using doubly labeled water methodology | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Resting energy expenditure (REE) | Assessed by indirect calorimetry using respiratory gas exchange methodology with a ventilated hood system | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Physical activity level, (moderate to vigorous) | Total minutes of moderate- to vigorous-intensity physical activity, assessed by accelerometry | Measurements made daily during 2 weeks at PWL, 2 weeks at END, and alternating non-assessment weeks of the residential phase and integrated into a unified outcome | 
| Insulin sensitivity | Assessed by frequently-sampled oral glucose tolerance test [OGTT], calculated using plasma insulin and glucose values | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Insulin secretion | Assessed by frequently-sampled oral glucose tolerance test [OGTT], using plasma insulin at 30 minutes following the dose of dextrose | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Glycemic control | Hemoglobin A1c [HbA1c] | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Total cholesterol | Chronic disease risk factor | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| HDL-cholesterol | Chronic disease risk factor | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| LDL-cholesterol | Chronic disease risk factor | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Non-HDL cholesterol | Chronic disease risk factor | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Triglycerides | Chronic disease risk factor | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Plasminogen Activator Inhibitor-1 [PAI-1] | Indicator of coagulopathy | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| High-sensitivity C-reactive protein [hsCRP] | Indicator of chronic inflammation | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Uric acid | Indicator of risk for kidney stones, measured in blood | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Systolic blood pressure | Assessed by auscultation, mmHg | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Diastolic blood pressure | Assessed by auscultation, mmHg | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Thyroxine (T4) | Thyroid function | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Free T4 | Thyroid function | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Thyroid stimulating hormone [TSH] | Thyroid function | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Insulin-like growth factor-1 [IGF-1] | Growth hormone action | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Urine cortisol | Stress hormone, assessed using 24-hour urine collection | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Urine catecholamines | Stress hormone, assessed using 24-hour urine collection | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Leptin | Adipokine | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Total Adiponectin | Adipokine | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| High-molecular weight adiponectin | Adipokine | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Sleep | Total sleep time, sleep onset latency, wake after sleep onset, and sleep efficiency, assessed by accelerometry | Measurements made daily during 2 weeks at PWL, 2 weeks at END, and alternating non-assessment weeks of the residential phase and integrated into a unified outcome | 
| Blood glucose | Assessed by continuous glucose monitoring (CGM) | Measurements made daily during residential phase (0 to 10 weeks) and integrated into a unified outcome | 
| Ghrelin | Hormonal Control of Appetite | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Body Circumference | Assessed using a 3D body scan | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 
| Post-prandial energy expenditure and respiratory quotient | Optional testing, assessed by indirect calorimetry using respiratory gas exchange | Single assessment in weeks 6 to 8 of residential study | 
| Activation of insulin signaling pathways | Assessed by immunohistochemistry of phosphorylated insulin receptor and signaling proteins | Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Body composition, Feeding study, Ketogenic diet, Weight loss, Energy Expenditure