Abstract 13458: Fatty Acid Binding Protein 4 and 5 Play a Crucial Role in Adaptive Response to Prolonged Fasting and Cold Exposure in Mice
During prolonged fasting, most tissues including the heart and skeletal muscle heavily rely on utilization of fatty acids (FA) released from adipose tissue, while glucose utilization is minimized. We have recently shown that FA binding protein 4 (FABP4) and FABP5, cytosolic FA chaperones abundantly expressed in adipocytes and macrophages, are prominently expressed in capillary endothelium in the heart and skeletal muscle, and that mice doubly deficient for FABP4/5 (DKO mice) exhibit defective uptake of FA with compensatory up-regulation of glucose consumption during fasting. Here we show that deletion of FABP4/5 resulted in marked perturbation of metabolism in response to prolonged fasting. Blood glucose level was reduced whereas levels of non-esterified FA (NEFA) and ketone bodies were markedly increased during fasting. Uptake of 125I-BMIPP FA analogue in DKO liver was markedly increased after fasting. Consistent with increased influx of NEFA into liver, DKO mice showed marked hepatic steatosis after 48-hour fasting. Higher rate of FA oxidation was conserved in DKO liver in both the fed and fasted states. Although gluconeogenesis was conserved shortly after fasting, materials for gluconeogenesis were exhausted during prolonged fasting, resulting in insufficient gluconeogenesis and enhanced hypoglycemia. These metabolic responses to prolonged fasting in DKO mice were readily reversed by re-feeding. Furthermore, body temperature of DKO mice fasted for 20 hours was rapidly decreased below 25°C when exposed to 4°C, which could be due to lower supply of glucose to heat-generating peripheral tissues such as skeletal muscle and brown adipose tissue. These data strongly suggest that maladaptive response to fasting in DKO mice occur as a result of increased influx of NEFA into liver and pronounced hypoglycemia. Together with our previous study, the metabolic consequence found in this study is likely to be attributed to an impairment of FA uptake and compensatory up-regulation of glucose consumption in the heart and skeletal muscle. Therefore, our data provide the proof that peripheral uptake of FA via capillary endothelial FABP4/5 is crucial for systemic metabolism and may establish FABP4/5 as potential new targets for the modulation of energy homeostasis.
- © 2013 by American Heart Association, Inc.