The purpose of this study is to understand how weight loss by a very low fat plant-based diet with an exercise program affects metabolic and cardiovascular health in overweight adults at high risk for disease. Outcome measures will include assessment of insulin sensitivity, β-cell function, body fat distribution, skeletal muscle and adipose tissue biology, cardiovascular function, cardiorespiratory fitness, muscular strength, immune function, and the gut microbiome.

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-forward 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 plus unsupervised exercise sessions performed 2 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, muscle biopsies, body composition scans, blood tests, and urine and stool collections.

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 obesity, prediabetes and insulin resistance, 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 proteome, insulin sensitivity, beta-cell function, systemic inflammation, 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 calorie restriction-induced weight loss plus exercise on a series of key outcome measures, and 2) the potential additional benefit of adding regular exercise to a plant-forward diet.

Inclusion Criteria:

• Age ≥18 and ≤55 years
• BMI ≥30.0 and ≤50.0 kg/m²
• HbA1c ≥5.7%, or fasting plasma glucose concentration ≥100 mg/dl, or 2-hr OGTT plasma glucose concentration ≥140 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, vegetarians, those with lactose intolerance and/or severe aversions/sensitivities to eggs, fish, nuts, wheat and soy, and/or any individuals with food allergies that induce an anaphylactic response
• 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

All of the data from individual subjects will be maintained confidentially and their names and identities will not be disclosed in any published document.