Abstract
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.
Highlights
Liver fatty acid-binding protein (LFABP) binds long-chain fatty acids with high affinity and is abundantly expressed in the liver and small intestine
Similar results were observed with high fat–fed mice in both fed and fasting states, with LFABPϪ/Ϫ mice showing an approximate doubling of total running distance compared with WT (Fig. 1, C and D)
Exercise capacity is affected by many physiological factors that support sustained energy production for muscle contraction, mitochondrial function and substrate availability [26, 29, 30]
Summary
LFABP؊/؊ mice are protected from high-fat feeding–induced decline in exercise capacity. In response to high-fat feeding, WT mice showed a marked decrease in exercise capacity, whereas LFABPϪ/Ϫ mice maintained their exercise capacity at a comparable level to their low fat–fed counterparts (Fig. 1, A and B). Compared with WT mice, LFABPϪ/Ϫ mice had significantly higher levels of both muscle glycogen and IMTG (Fig. 2, A and B), providing an increased substrate availability for energy production. Compared with WT mice, LFABPϪ/Ϫ mice had a higher rate of 14CO2 production from [14C]oleic acid in skeletal muscle (Fig. 3E), indicating greater capacity for complete fatty acid oxidation. The basal respiration was similar between the genotypes, LFABPϪ/Ϫ myoblasts showed a greater respiratory capacity compared with WT myoblasts, further supporting the improved mitochondrial function in high fat–fed LFABPϪ/Ϫ mice (Fig. 3, G and H). Metabolites were determined by LC-MS/MS. *, p Ͻ 0.05 between WT and LFABPϪ/Ϫ; **, 0.05 Ͻ p Ͻ 0.1 between WT and LFABPϪ/Ϫ
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