Fat and fit: metabolic changes in skeletal muscle of liver fatty acid-binding protein knockout mice
Creators: name: Xu, Heli
Publisher: name: No Publisher Supplied
Year: 2019

description: Liver fatty acid-binding protein (LFABP, FABP1) is abundantly expressed in the liver and small intestine, and thought to facilitate hepatic and intestinal lipid trafficking into various metabolic pathways with its high binding affinity for long chain fatty acids. Moreover, LFABP has also been implicated in regulating systemic energy homeostasis based on studies of LFABP null (LFABP-/-) mice. We and others have previously reported that LFABP-/- mice exhibit greater body weight gain and body fat mass in response to high fat feeding compared with wild-type (WT) mice. Despite being more obese, however, LFABP-/- mice were protected from high fat feeding-induced decline in exercise capacity, showing an approximate doubling of running distance compared with WT mice on the high fat diet. In studies aimed at understanding the metabolic changes in skeletal muscle underlying this surprising exercise phenotype in LFABP-/- mice, we found significantly higher triglyceride and glycogen content, as well as increased mitochondrial enzyme activities and fatty acid oxidation capacity in the resting muscles of LFABP-/- mice, suggesting a greater substrate storage and mitochondrial function at resting state. During a low intensity exercise, LFABP-/- mice showed a preference for carbohydrate utilization in the first 10 min of the exercise and switched to a higher lipid utilization compared with WT during the rest 10 min of exercise, with greater exercise-dependent decreases in muscle glycogen stores and elevated free fatty acid in the plasma after exercise. Using cellular bioenergetics measurements, primary myoblasts from high fat-fed LFABP-/- mice showed a higher respiratory capacity compared with WT mice, supporting the increased exercise capacity of LFABP-/- mice. Interestingly, primary myotubes from chow-fed mice treated with fatty acids only showed modest difference between the genotypes, suggesting that apart from a high concentration of plasma FAs, other circulating mediators may be required for the improved muscle energy metabolism in high fat fed-LFABP-/- mice. In examining potential interorgan signaling possibilities, we found similar insulin sensitivity in skeletal muscle between the genotypes, suggesting an insulin-independent mechanism mediating the muscle metabolic changes in LFABP-/- mice. Moreover, we found decreased FGF21 expression levels in the liver and trending lower FGF21 levels in the plasma of LFABP-/- mice, despite our previous report that LFABP-/- mice showed trending higher plasma levels of adiponectin, a downstream target of FGF21. However, we found similar FGF21 sensitivity in epidydimal adipose tissues between the genotypes and trending lower expression levels of adiponectin in the epidydimal adipose tissues, suggesting that FGF21-meidated adiponectin production and secretion may be enhanced in other fat depots. Overall, muscle metabolic reprogramming in LFABP-/- mice underlies their resistance to high fat feeding-induced decline in exercise capacity, including increased substrate availability and improved mitochondrial function in response to high fat diets. Since LFABP is not expressed in the muscle, these alterations in muscle energy metabolism of LFABP-/- mice appear to be induced signaling molecules in the plasma, possibly involving adiponectin.