Obesity and diabetes are major and growing public health issues that affect all Western countries. Cardiac high-energy phosphate metabolism, measured non-invasively as the phosphocreatine (PCr)/ATP ratio using ³¹Phosphorus magnetic resonance spectroscopy, is abnormal in patients with obesity and/or diabetes. However, the cellular mechanism causing low cardiac PCr/ATP is unclear and whether low energetics are related to contractile dysfunction is unknown. Plasma norepinephrine concentrations are increased in both conditions. Activation of the sympathetic nervous system causes adipose tissue lipolysis, which elevates circulating free fatty acid concentrations. High circulating free fatty acid concentrations are associated with a shift in substrate preference towards free fatty acid oxidation, with greater myocardial oxygen consumption, in the obese or diabetic heart. We have studied the link between abnormal circulating free fatty acid concentrations and low cardiac PCr/ATP ratios in obese and diabetic patients and found that they were correlated. These results suggest that the increased circulating free fatty acid concentrations lead to increased myocardial free fatty acid uptake, which uncouples oxidative phosphorylation in mitochondria and thereby impairs energy metabolism in heart. Thus, changes in substrate availability may lead to a myopathy in patients who are obese or have diabetes. A therapy that reduces circulating free fatty acid concentrations or inhibits mitochondrial free fatty acid uptake and/or oxidation may enhance high-energy phosphate metabolism and thereby prevent cardiac contractile dysfunction.