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.