The FB4 trial has been terminated due to COVID-19.

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.

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).

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

Assessors conducting analyses of biospecimens, laboratory personnel, DXA technologists, and research nurses were blinded to random group assignment. They were not involved in the randomization process or any aspects of the intervention. The statistical team worked with masked labels for the diet arms.