Regulation of fasting fuel metabolism by toll-like receptor 4.
OBJECTIVE
Toll-like receptor 4 (TLR4) has been reported to induce insulin resistance through inflammation in high-fat-fed mice. However, the physiological role of TLR4 in metabolism is unknown. Here, we investigated the involvement of TLR4 in fasting metabolism.


METHODS
Wild-type and TLR4 deficient (TLR4(-/-)) mice were either fed or fasted for 24 h. Glucose and lipid levels in circulation and tissues were measured. Glucose and lipid metabolism in tissues, as well as the expression of related enzymes, was examined.


RESULTS
Mice lacking TLR4 displayed aggravated fasting hypoglycemia, along with normal hepatic gluconeogenesis, but reversed activity of pyruvate dehydrogenase complex (PDC) in skeletal muscle, which might account for the fasting hypoglycemia. TLR4(-/-) mice also exhibited higher lipid levels in circulation and skeletal muscle after fasting and reversed expression of lipogenic enzymes in skeletal muscle but not liver and adipose tissue. Adipose tissue lipolysis is normal and muscle fatty acid oxidation is increased in TLR4(-/-) mice after fasting. Inhibition of fatty acid synthesis in TLR4(-/-) mice abolished hyperlipidemia, hypoglycemia, and PDC activity increase, suggesting that TLR4-dependent inhibition of muscle lipogenesis may contribute to glucose and lipid homeostasis during fasting. Further studies showed that TLR4 deficiency had no effect on insulin signaling and muscle proinflammatory cytokine production in response to fasting.


CONCLUSIONS
These data suggest that TLR4 plays a critical role in glucose and lipid metabolism independent of insulin during fasting and identify a novel physiological role for TLR4 in fuel homeostasis.
Pang
Shanshan
S
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Tang
Haiqing
H
Zhuo
Shu
S
Zang
Ying Qin
YQ
Le
Yingying
Y
D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D002245:Carbon Dioxide / Q000032:analysis; D018076:DNA, Complementary / Q000235:genetics; D005215:Fasting / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis; D007003:Hypoglycemia / Q000235:genetics; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology; D010101:Oxygen Consumption; D016133:Polymerase Chain Reaction; D012313:RNA / Q000187:drug effects / Q000302:isolation & purification; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D018076:DNA, Complementary; D005227:Fatty Acids; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D002245:Carbon Dioxide; D012313:RNA