Obesity is responsible for the death of 300,000 Americans a year. Yet, the effects of over-nutrition on the heart are not well understood. We therefore propose to examine "footprints" of obesity in the heart, and to identify mechanisms leading to impaired cardiac function in animal models, as well as in clinically obese patients undergoing gastric bypass surgery. Special emphasis is placed on the myocardial consequences of deranged glucose and fatty acid metabolism and their potential reversal. The broad objective of this proposal is to test the hypothesis that abnormal accumulation of glucose and fatty acid metabolites results from a loss of synchronization of substrate uptake and oxidation, and leads to glucolipotoxicity and to contractile dysfunction in the heart. The first specific aim will define the process by which excessive fuel supply (beyond the storage capacity of adipocytes) results in accumulation of lipotoxic compounds in the heart and in other organs (e.g. skeletal muscle). In genetic and diet-induced rat models of obesity we shall define the time course of adaptation and maladaptation to excess substrate availability. We shall also define the time course of reversal of obesity-induced changes by food restriction or surgical intervention (gastric bypass). The second specific aim will address potential mechanisms of glucolipotoxicity in heart, as well as skeletal muscle. We shall examine gene expression, PKC activity, protein glycosylation, protein ubiquitinization, and programmed cell death. Selective activation of these different pathways may play a significant role in glucolipotoxicity. The third specific aim will apply insights gained from animal experiments to correlates of glucolipotoxicity in humans. We will test the hypothesis that weight loss reverses the maladaptive response in patients undergoing bariatric weight loss surgery. We will define metabolic indices (BMI, insulin resistance, blood pressure, lipid profile, adipokine levels) and various indices of cardiac function (e.g. echocardiography) in tandem with skeletal muscle biopsies before, as well as three and nine months after surgery. Our long-term goals are to describe metabolic adaptation and maladaptation of the heart in clinically relevant obesity, to transform the concept of glucolipotoxicity from an operational definition to a concrete physiological principle, and to establish a rationale for more effective treatment of obese patients with heart failure.