Abstract
Hypothermia is rapidly induced during cold exposure when thermoregulatory mechanisms, including fatty acid (FA) utilization, are disturbed. FA binding protein 4 (FABP4) and FABP5, which are abundantly expressed in adipose tissues and macrophages, have been identified as key molecules in the pathogenesis of overnutrition-related diseases, such as insulin resistance and atherosclerosis. We have recently shown that FABP4/5 are prominently expressed in capillary endothelial cells in the heart and skeletal muscle and play a crucial role in FA utilization in these tissues. However, the role of FABP4/5 in thermogenesis remains to be determined. In this study, we showed that thermogenesis is severely impaired in mice lacking both FABP4 and FABP5 (DKO mice), as manifested shortly after cold exposure during fasting. In DKO mice, the storage of both triacylglycerol in brown adipose tissue (BAT) and glycogen in skeletal muscle (SkM) was nearly depleted after fasting, and a biodistribution analysis using 125I-BMIPP revealed that non-esterified FAs (NEFAs) are not efficiently taken up by BAT despite the robustly elevated levels of serum NEFAs. In addition to the severe hypoglycemia observed in DKO mice during fasting, cold exposure did not induce the uptake of glucose analogue 18F-FDG by BAT. These findings strongly suggest that DKO mice exhibit pronounced hypothermia after fasting due to the depletion of energy storage in BAT and SkM and the reduced supply of energy substrates to these tissues. In conclusion, FABP4/5 play an indispensable role in thermogenesis in BAT and SkM. Our study underscores the importance of FABP4/5 for overcoming life-threatening environments, such as cold and starvation.
Highlights
The endothelium has emerged as a dynamic organ that regulates the systemic lipid metabolism and insulin sensitivity, and as such, endothelial dysfunction contributes to the pathogenesis of overnutrition-related metabolic disorders, such as type 2 diabetes and metabolic syndrome [1,2]
These researchers demonstrated that the chemical inhibition of the function of FA binding protein 4 (FABP4) prevents the insulin resistance and atherosclerosis induced by a high-fat diet in mice [8]
The present study provides several lines of evidence indicating that FABP4/5 play a crucial role in thermogenesis, which is
Summary
The endothelium has emerged as a dynamic organ that regulates the systemic lipid metabolism and insulin sensitivity, and as such, endothelial dysfunction contributes to the pathogenesis of overnutrition-related metabolic disorders, such as type 2 diabetes and metabolic syndrome [1,2]. PPARc plays a critical role as a master regulator of the transcription of these genes [3,4], and vascular endothelial growth factor (VEGF)B secreted from cardiac and skeletal muscle and brown adipose tissue produces fatty acid transport proteins via VEGF receptor 1 and the co-receptor neuropilin 1 in capillary endothelial cells [5,6]. These molecules promote FA transport from the blood, across endothelial cells, to myocytes and adipocytes, which are highly oxidative cells. We have recently shown that FABP4/5 are clearly expressed in capillary endothelial cells in the heart and skeletal muscle [9]
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