• Association between AO-related changes in myocardial fatty acid metabolism and abnormalities in left ventricular systolic and diastolic function [ Time Frame: Measured at Year 5 ] [ Designated as safety issue: No ]
  
• Effect of significant weight loss (10% of body weight) on myocardial fatty acid and glucose metabolism in relation to whole-body fatty acid and glucose kinetics [ Time Frame: Measured at Year 5 ] [ Designated as safety issue: No ]
  
• Effects of changes in myocardial substrate metabolism that occur with weight loss on left ventricular systolic and diastolic function [ Time Frame: Measured at Year 5 ] [ Designated as safety issue: No ]
  

• Alterations in the response of myocardial fatty acid and glucose metabolism to increased insulin availability and how the potential alterations relate to whole-body fatty acid and glucose kinetics [ Time Frame: Measured at Year 5 ] [ Designated as safety issue: No ]
  
• Impact of increased delivery of fatty acids on myocardial fatty acid and glucose metabolism in relation to whole body fatty acid and glucose kinetics [ Time Frame: Measured at Year 5 ] [ Designated as safety issue: No ]
  
• Association between the myocardial metabolic response and changes in left ventricular systolic and diastolic function [ Time Frame: Measured at Year 5 ] [ Designated as safety issue: No ]
  

Obesity is defined as having a high amount of excess body fat. Millions of people worldwide meet the criteria for obesity, making it one of the most pressing current health issues. The more body fat a person has, the more susceptible that person is to a number of life threatening diseases, including heart disease, type 2 diabetes, gallstones, certain cancers, and high blood pressure. A variety of factors can lead to obesity. These factors include family history and genetics, physical inactivity, metabolism, hormone imbalance, and environment. Past research suggests that an increased availability of fats in the body leads to increased fat uptake by the heart. The heart only needs a certain amount of fat for energy, which leaves the remaining fat in the heart tissue, possibly impairing proper heart function. However, more information on the mechanisms behind the effects of fats on heart metabolism is needed. This study will evaluate the impact of AO on the human heart's use of fats for energy and on heart function.

This study will enroll both overweight and lean participants who will attend 4 to 7 study visits. Visit 1 will consist of various screening tests, including a medical history, physical exam, pregnancy test if applicable, routine blood test, and an echocardiogram (ECHO) performed before and during exercise.

Visit 2 will consist of an abdominal fat and insulin sensitivity study. This will entail a magnetic resonance imaging (MRI) test to image the heart and stomach, a dual energy x-ray absorptiometry (DEXA) scan to measure total body fat and muscle content, and an insulin sensitivity test to measure how well the hormone insulin controls blood sugar. The latter test will require multiple blood draws over a 3-hour period.

Visits 3 and 4 will occur over a 2-week period. Both visits will consist of an overnight stay at the General Clinical Research Center (GCRC) followed by a day of imaging studies. During Visit 3, participants will first undergo a 4-hour whole body metabolism study, which will include injection of a nonradioactive tracer through previously placed IVs, blood draws, and breathing into a machine for approximately 15 minutes. Participants will then undergo a positron emission tomographic (PET) heart metabolism study, which will also involve tracer injections and blood draws. A resting ECHO test will also be done during the PET study. Participants will be asked for permission to store a sample of their blood for a period of up to 10 years to be used in future research studies on the heart. During Visit 4, participants will undergo repeat tests from the third visit, except the PET study will evaluate the heart's ability to use sugars instead of fats. This will complete the study visits for all lean participants and some overweight participants and will entail 4 weeks of participation.

Overweight participants may be asked to attend an additional three study visits during an 8-month weight management program at Washington University School of Medicine. Participants will aim to lose 10% of their body weight over a 6-month period and to maintain that weight loss for another 1- to 2-month stabilization period. At the end of the stabilization period, participants will undergo repeat abdominal fat and insulin sensitivity studies during Visit 5, repeat whole body metabolism and heart metabolism studies during Visit 6, and repeat whole body metabolism and glucose heart metabolism studies during Visit 7.