Liver fatty acid-binding protein (L-Fabp) regulates murine hepatic
fatty acid trafficking in response to fasting. In this study, we show that L-Fabp(-/-) mice fed a high-fat Western diet for up to 18 weeks are less obese and accumulate less hepatic
triglyceride than C57BL/6J controls. Paradoxically, both control and L-Fabp(-/-) mice manifested comparable
glucose intolerance and
insulin resistance when fed a Western diet. Protection against
obesity in Western diet-fed L-Fabp(-/-) mice was not due to discernable changes in food intake, fat malabsorption, or heat production, although intestinal
lipid secretion kinetics were significantly slower in both chow-fed and Western diet-fed L-Fabp(-/-) mice. By contrast, there was a significant increase in the respiratory exchange ratio in L-Fabp(-/-) mice, suggesting a shift in energy substrate use from fat to
carbohydrate, findings supported by an approximately threefold increase in serum
lactate. Microarray analysis revealed increased expression of genes involved in
lipid synthesis (
fatty acid synthase,
squalene epoxidase, hydroxy-methylglutaryl
coenzyme A reductase), while genes involved in glycolysis (
glucokinase and
glycerol kinase) were decreased in L-Fabp(-/-) mice.
Fatty acid synthase expression was also increased in the skeletal muscle of L-Fabp(-/-) mice. In conclusion, L-Fabp may function as a metabolic sensor in regulating
lipid homeostasis. We suggest that L-Fabp(-/-) mice are protected against Western diet-induced
obesity and hepatic steatosis through a series of adaptations in both hepatic and extrahepatic energy substrate use. (HEPATOLOGY 2006;44:1191-1205.).