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

Overview

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.

Full Title of Study: “Macronutrients and Body Fat Accumulation: A Mechanistic Feeding Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Investigator, Outcomes Assessor)
  • Study Primary Completion Date: May 3, 2020

Detailed Description

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).

Interventions

  • Behavioral: Feeding Study
    • Food provision throughout the study: 1) Run-In Phase (VLC diet, weight loss); 2) Residential Phase (3 different test diets, weight-loss maintenance).

Arms, Groups and Cohorts

  • Experimental: Very-Low Carbohydrate Diet
    • Feeding study. Dietary composition (approximately): 75% fat
  • Experimental: High-Carbohydrate Low-Sugar Diet
    • Feeding study. Dietary composition (approximately): 25% fat 0% added sugars.
  • Experimental: High-Carbohydrate High-Sugar Diet
    • Feeding study. Dietary composition (approximately): 25% fat, 20% added sugars.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 50 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Boston Children’s Hospital
  • Collaborator
    • Indiana University
  • Provider of Information About this Clinical Study
    • Principal Investigator: David S. Ludwig, MD, PhD, Co-Director, New Balance Foundation Obesity Prevention Center – Boston Children’s Hospital
  • Overall Official(s)
    • David S Ludwig, MD, PhD, Principal Investigator, Boston Children’s Hospital
    • David B Allison, PhD, Principal Investigator, Indiana University, Bloomington
    • Cara B Ebbeling, PhD, Study Director, Boston Children’s Hospital

References

Ludwig DS, Friedman MI. Increasing adiposity: consequence or cause of overeating? JAMA. 2014 Jun 4;311(21):2167-8. doi: 10.1001/jama.2014.4133. No abstract available. Erratum In: JAMA. 2014 Jun 4;311(21):2168.

Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, Ludwig DS. Effects of dietary composition on energy expenditure during weight-loss maintenance. JAMA. 2012 Jun 27;307(24):2627-34. doi: 10.1001/jama.2012.6607.

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