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

Macronutrients and Body Fat Accumulation: A Mechanistic Feeding Study

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.

Study Overview

• Status: Terminated
• Conditions: Obesity
• Intervention / Treatment: Behavioral: Feeding Study

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).

• Study Type: Interventional
• Enrollment (Actual): 166
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Ashland, Massachusetts, United States, 01721
      • Warren Conference Center and Inn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Very-Low Carbohydrate Diet; Feeding study. Dietary composition (approximately): 75% fat	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).; Other Names: weight loss, weight-loss maintenance
Experimental: High-Carbohydrate Low-Sugar Diet; Feeding study. Dietary composition (approximately): 25% fat 0% added sugars.	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).; Other Names: weight loss, weight-loss maintenance
Experimental: High-Carbohydrate High-Sugar Diet; Feeding study. Dietary composition (approximately): 25% fat, 20% added sugars.	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).; Other Names: weight loss, weight-loss maintenance

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
1,5-anhydroglucitol (1,5-AG)	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Lipoprotein particle subfraction distribution	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Fibrinogen	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Interleukin-6 (IL-6)	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Reverse triiodothyronine (rT3)	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Insulin-like growth factor-binding protein 3 (IGF-BP3)	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Luteinizing hormone (LH)	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Follicle stimulating hormone (FSH)	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Estradiol (E2)	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Testosterone (TST, total)	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Testosterone (TST, free)	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Metabolomics profile	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Biomarker of cholesterol synthesis	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Biomarker of cholesterol absorption	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
MicroRNA	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Gut microbiome	Possible future analyses of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Demographics (mediator/modifier)	Baseline covariate	Pre-weight loss baseline
Body composition (mediator/modifier)	Baseline covariate	Pre-weight loss baseline
Measure of glucose homeostasis (insulin-30) (mediator/modifier)	Baseline covariate	Pre-weight loss baseline
Measure of glucose homeostasis (insulin sensitivity) (mediator/modifier)	Baseline covariate	Pre-weight loss baseline
Measure of glucose homeostasis (glycemic control) (mediator/modifier)	Baseline covariate	Pre-weight loss baseline
Obesity related genetic risk (mediator/modifier)	Baseline covariate	Pre-weight loss baseline
Body composition (mediator/modifier)	Time varying covariate	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Measure of glucose homeostasis (insulin-30) (mediator/modifier)	Time varying covariate	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Measure of glucose homeostasis (insulin sensitivity) (mediator/modifier)	Time varying covariate	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Measure of glucose homeostasis (glycemic control) (mediator/modifier)	Time varying covariate	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Physical activity level (moderate to vigorous) (mediator/modifier)	Time varying covariate for 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
Sex Hormone-Binding Globulin (SHBG)	Possible future analysis of archived specimen	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Urinary nitrogen	Archived for future analysis	End of residential (END, 10 weeks)
Glucagon-like peptide-1 (GLP-1)	Possible future analyses of archived samples	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Glucose-dependent insulinotropic polypeptide (GIP)	Possible future analyses of archived samples	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Glucagon	Possible future analyses of archived samples	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Oxytocin	Possible future analyses of archived samples	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)
Oxyntomodulin	Possible future analyses of archived samples	Change from post-weight loss (PWL, 0 weeks) to end of residential study (END, 10 weeks)

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: University of Alabama at Birmingham; Indiana University; Baylor University; Framingham State University
• Investigators: Principal Investigator: David B Allison, PhD, Indiana University Bloomington; Study Director: Cara B Ebbeling, PhD, Boston Children's Hospital

Publications and helpful links

General Publications

• 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.
• Wong JMW, Yu S, Ma C, Mehta T, Dickinson SL, Allison DB, Heymsfield SB, Ebbeling CB, Ludwig DS. Stimulated Insulin Secretion Predicts Changes in Body Composition Following Weight Loss in Adults with High BMI. J Nutr. 2022 Mar 3;152(3):655-662. doi: 10.1093/jn/nxab315.
• 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.
• Jansen LT, Yang N, Wong JMW, Mehta T, Allison DB, Ludwig DS, Ebbeling CB. Prolonged Glycemic Adaptation Following Transition From a Low- to High-Carbohydrate Diet: A Randomized Controlled Feeding Trial. Diabetes Care. 2022 Mar 1;45(3):576-584. doi: 10.2337/dc21-1970.

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2018
• Primary Completion (Actual): May 3, 2020
• Study Completion (Actual): May 3, 2020

Study Registration Dates

• First Submitted: December 29, 2017
• First Submitted That Met QC Criteria: January 3, 2018
• First Posted (Actual): January 9, 2018

Study Record Updates

• Last Update Posted (Actual): June 18, 2021
• Last Update Submitted That Met QC Criteria: June 17, 2021
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Weight loss; Body composition; Energy Expenditure; Ketogenic diet; Feeding study
• Other Study ID Numbers: IRB-P00026977

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No