Effects of a Calorie Restricted, Very Low Fat Plant-based Diet and Multi-component Exercise Program on Metabolic Health

Reduced energy intake and increased physical activity have profound effects on
cardiometabolic health as assessed by insulin sensitivity, β-cell function, serum lipids,
intra-abdominal fat mass, intrahepatic triglyceride content, and blood pressure, and is the
cornerstone of treatment for people with obesity. However, the specific additional
therapeutic effects of regular exercise in conjunction with diet-induced weight loss are not
clear. In addition, the optimal dietary macronutrient composition needed to reduce
cardiometabolic risk is not known. The use of a very low fat, plant-based (PB) diet is
becoming increasingly popular to treat people with obesity and is the only diet therapy that
is reimbursed by Medicare in the treatment of people with coronary heart disease.

Participants will undergo nutritional counseling and have supervised exercise training 4 days
per week until 7-10% weight loss is achieved. Meals will be provided and food diaries will be
kept during weight loss. Tests before and after the intervention will include muscular
strength and aerobic fitness, cardiovascular assessments, glucose tolerance tests,
hyperinsulinemic euglycemic clamp test for insulin sensitivity, heavy water metabolism,
resting energy expenditure/metabolic rate, muscle and fat biopsies, body composition scans,
blood tests, and urine and stool collection.

The overarching goal of this project is to conduct a comprehensive characterization of weight
loss induced by using a PB diet with regular exercise in people with MAO, followed by a
comparison of the effects of this study with those from another study that is evaluating the
effect of the same amount of weight loss induced by using a PB diet alone, without exercise.
Specifically, we will evaluate changes in body composition, body fat distribution,
cardiopulmonary function, muscle strength, the plasma metabolome, insulin sensitivity,
beta-cell function, systemic and adipose tissue inflammation and immune system function,
adipose tissue and muscle cellular metabolic pathways, and the gut microbiome to determine
cellular, multiorgan, and whole-body effects of PB diet alone and PB diet plus exercise.
Accordingly, this study will fill two important gaps in our knowledge that have considerable
physiological and clinical significance; the data from this study will provide: 1) a better
understanding of the effects of a PB diet plus exercise on a series of key outcome measures,
and 2) the potential additional benefit of adding regular exercise to a PB diet.

Inclusion Criteria:

- Age ≥18 and ≤55 years

- BMI ≥30.0 and ≤50.0 kg/m²

- IHTG content ≥5.6%; HbA1c ≥5.7%, or fasting plasma glucose concentration ≥100 mg/dl,
or 2-hr OGTT plasma glucose concentration ≥140 mg/dl OR HbA1c ≥5.8% and 2-hr OGTT
plasma glucose concentration ≥150 mg/dl

Exclusion Criteria:

- Medical, surgical, or biological menopause

- Previous bariatric surgery

- Structured exercise >2 days/week for ≥35 minutes of intense exercise (e.g., jogging,
activity that causes heavy breathing and sweating) or ≥150 min per week of structured
exercise (e.g., brisk walking)

- Unstable weight (>4% change during the last 2 months before entering the study)

- Significant organ system dysfunction (e.g., diabetes requiring medications, severe
pulmonary, kidney or cardiovascular disease)

- Cancer or cancer that has been in remission for <5 years

- Polycystic ovary syndrome

- Major psychiatric illness

- Conditions that render subject unable to complete all testing procedures (e.g., severe
ambulatory impairments, limb amputations, or metal implants that interfere with
imaging procedures; coagulation disorders)

- Use of medications that are known to affect the study outcome measures (e.g.,
steroids, non-statin lipid lowering medications) or increase the risk of study
procedures (e.g., anticoagulants) and that cannot be temporarily discontinued for this
study

- Use of antibiotics in last 60 days

- Smoke cigarettes, use marijuana >2 x/week, or use of illegal drugs

- Men who consume >21 units (e.g. glass of wine or bottle of beer) of alcohol per week
and women who consume >14 units of alcohol per week

- Pregnant or lactating women

- Vegans

- Persons who are not able to grant voluntary informed consent

- Persons who are unable or unwilling to follow the study protocol or who, for any
reason, the research team considers not an appropriate candidate for this study,
including non-compliance with screening appointments or study visits