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Regulation of fasting fuel metabolism by toll-like receptor 4.

Pang S, Tang H, Zhuo S, Zang YQ, Le Y - Diabetes (2010)

Bottom Line: 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.Further studies showed that TLR4 deficiency had no effect on insulin signaling and muscle proinflammatory cytokine production in response to fasting.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT

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.

Research design and 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.

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Related in: MedlinePlus

Reversed PDC activity and glycolytic enzymes expression in skeletal muscle of −/− mice during fasting. Male wild-type (WT) and TLR4−/− mice were either fed or fasted for 24 h. A: PDC activity in skeletal muscle. B: mRNA levels of PDC components in skeletal muscle. C: mRNA levels of rate-limiting enzymes of glycolysis in skeletal muscle. All data shown are means ± SEM; n = 4–7. *P < 0.05 vs. wild-type mice.
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Figure 2: Reversed PDC activity and glycolytic enzymes expression in skeletal muscle of −/− mice during fasting. Male wild-type (WT) and TLR4−/− mice were either fed or fasted for 24 h. A: PDC activity in skeletal muscle. B: mRNA levels of PDC components in skeletal muscle. C: mRNA levels of rate-limiting enzymes of glycolysis in skeletal muscle. All data shown are means ± SEM; n = 4–7. *P < 0.05 vs. wild-type mice.

Mentions: During fasting, glucose could also be spared by blocking the irreversible net loss of glucose in skeletal muscle through PDC inhibition (3,4). PDC consists of three enzymes: pyruvate dehydrogenase (PDHA1), dihydrolipoamide acetyltransferase (DLAT), and dihydrolipoamide dehydrogenase (DLD). We found that fasting significantly inhibited PDC activity in skeletal muscle of wild-type mice. Notably, the inhibition was largely reversed by TLR4 deletion (Fig. 2A). In addition, fasting inhibited the mRNA expression of all three enzymes of PDC in wild-type mice, whereas it only inhibited the expression of DLAT in TLR4−/− mice (Fig. 2B). These results suggest that unsuppressed PDC activity in skeletal muscle contributes at least partly to the severe fasting hypoglycemia in TLR4−/− mice. We also found that TLR4 deficiency reversed the mRNA levels of hexokinase 2 (HK2) and muscle phosphofructokinase (PFKM), two rate-limiting enzymes of glycolysis, in skeletal muscle during fasting (Fig. 2C), suggesting that glycolysis may also be reversed by TLR4 deficiency.


Regulation of fasting fuel metabolism by toll-like receptor 4.

Pang S, Tang H, Zhuo S, Zang YQ, Le Y - Diabetes (2010)

Reversed PDC activity and glycolytic enzymes expression in skeletal muscle of −/− mice during fasting. Male wild-type (WT) and TLR4−/− mice were either fed or fasted for 24 h. A: PDC activity in skeletal muscle. B: mRNA levels of PDC components in skeletal muscle. C: mRNA levels of rate-limiting enzymes of glycolysis in skeletal muscle. All data shown are means ± SEM; n = 4–7. *P < 0.05 vs. wild-type mice.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992764&req=5

Figure 2: Reversed PDC activity and glycolytic enzymes expression in skeletal muscle of −/− mice during fasting. Male wild-type (WT) and TLR4−/− mice were either fed or fasted for 24 h. A: PDC activity in skeletal muscle. B: mRNA levels of PDC components in skeletal muscle. C: mRNA levels of rate-limiting enzymes of glycolysis in skeletal muscle. All data shown are means ± SEM; n = 4–7. *P < 0.05 vs. wild-type mice.
Mentions: During fasting, glucose could also be spared by blocking the irreversible net loss of glucose in skeletal muscle through PDC inhibition (3,4). PDC consists of three enzymes: pyruvate dehydrogenase (PDHA1), dihydrolipoamide acetyltransferase (DLAT), and dihydrolipoamide dehydrogenase (DLD). We found that fasting significantly inhibited PDC activity in skeletal muscle of wild-type mice. Notably, the inhibition was largely reversed by TLR4 deletion (Fig. 2A). In addition, fasting inhibited the mRNA expression of all three enzymes of PDC in wild-type mice, whereas it only inhibited the expression of DLAT in TLR4−/− mice (Fig. 2B). These results suggest that unsuppressed PDC activity in skeletal muscle contributes at least partly to the severe fasting hypoglycemia in TLR4−/− mice. We also found that TLR4 deficiency reversed the mRNA levels of hexokinase 2 (HK2) and muscle phosphofructokinase (PFKM), two rate-limiting enzymes of glycolysis, in skeletal muscle during fasting (Fig. 2C), suggesting that glycolysis may also be reversed by TLR4 deficiency.

Bottom Line: 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.Further studies showed that TLR4 deficiency had no effect on insulin signaling and muscle proinflammatory cytokine production in response to fasting.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT

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.

Research design and 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.

Show MeSH
Related in: MedlinePlus