Muscle metabolic reprogramming underlies the resistance of liver fatty acid–binding protein (LFABP)-null mice to high-fat feeding–induced decline in exercise capacity

Liver fatty acid-binding protein (LFABP) binds long-chain fatty acids with high affinity and is abundantly expressed in the liver and small intestine. Although LFABP is thought to function in intracellular lipid trafficking, studies of LFABP-null (LFABP(?/?)) mice have also indicated a role in regulating systemic energy homeostasis. We and others have reported that LFABP(?/?) mice become more obese than wildtype (WT) mice upon high-fat feeding. Here, we show that despite increased body weight and fat mass, LFABP(?/?) mice are protected from a high-fat feeding?induced decline in exercise capacity, displaying an approximate doubling of running distance compared with WT mice. To understand this surprising exercise phenotype, we focused on metabolic alterations in the skeletal muscle due to LFABP ablation. Compared with WT mice, resting skeletal muscle of LFABP(?/?) mice had higher glycogen and intramuscular triglyceride levels as well as an increased fatty acid oxidation rate and greater mitochondrial enzyme activities, suggesting higher substrate availability and substrate utilization capacity. Dynamic changes in the respiratory exchange ratio during exercise indicated that LFABP(?/?) mice use more carbohydrate in the beginning of an exercise period and then switch to using lipids preferentially in the later stage. Consistently, LFABP(?/?) mice exhibited a greater decrease in muscle glycogen stores during exercise and elevated circulating free fatty acid levels postexercise. We conclude that, because LFABP is not expressed in muscle, its ablation appears to promote interorgan signaling that alters muscle substrate levels and metabolism, thereby contributing to the prevention of high-fat feeding?induced skeletal muscle impairment.