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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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TLR4 maintains fuel homeostasis during fasting. A and B: RPMI-1640 vehicle – or C75-treated male mice were fasted for 24 h and examined for PDC activity in skeletal muscle (A) and blood glucose levels (B). C and D: Measurements of oxygen consumption (C) and RQ (D) during fasting were carried out in the metabolic cage during fasting. All data shown are means ± SEM; n = 4–6. *P < 0.05, **P < 0.01, ***P < 0.001 vs. wild-type (WT) mice.
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Figure 6: TLR4 maintains fuel homeostasis during fasting. A and B: RPMI-1640 vehicle – or C75-treated male mice were fasted for 24 h and examined for PDC activity in skeletal muscle (A) and blood glucose levels (B). C and D: Measurements of oxygen consumption (C) and RQ (D) during fasting were carried out in the metabolic cage during fasting. All data shown are means ± SEM; n = 4–6. *P < 0.05, **P < 0.01, ***P < 0.001 vs. wild-type (WT) mice.

Mentions: Because de novo fatty acid synthesis uses acetyl-CoA oxidized from pyruvate as substrate, we asked whether TLR4 controls PDC activity and blood glucose levels through fatty acid synthesis regulation. As expected, we found that C75 treatment abolished the increase in muscle PDC activity and the severe fasting hypoglycemia resulting from TLR4 deficiency (Fig. 6A and 6B). These findings indicate that excess acetyl-CoA from increased muscle pyruvate oxidative decarboxylation in TLR4−/− mice may enter lipogenesis instead of TCA cycle. Thus, to better understand the effect of TLR4 deficiency on systemic fuel utilization, energy expenditure and respiratory quotient (RQ) were determined. During fasting, total energy expenditure was comparable in TLR4−/− mice and wild-type mice (Fig. 6C). The RQ of wild-type and TLR4−/− mice exhibited a similar pattern, with a rapid decrease after fasting followed by a steady level, indicating the shift of fuel utilization from carbohydrates to fat. However, the RQ of TLR4−/− mice decreased to a lower level than that of wild-type mice (Fig. 6D), indicating that more fat was used as energy. The lower RQ level in TLR4−/− mice is consistent with their increased FAO rates and supports that the products of pyruvate oxidative decarboxylation may be used for lipogenesis. Collectively, these data suggest an important role for TLR4 in maintaining the homeostasis between glucose and lipid fuel during fasting.


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

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

TLR4 maintains fuel homeostasis during fasting. A and B: RPMI-1640 vehicle – or C75-treated male mice were fasted for 24 h and examined for PDC activity in skeletal muscle (A) and blood glucose levels (B). C and D: Measurements of oxygen consumption (C) and RQ (D) during fasting were carried out in the metabolic cage during fasting. All data shown are means ± SEM; n = 4–6. *P < 0.05, **P < 0.01, ***P < 0.001 vs. wild-type (WT) mice.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 6: TLR4 maintains fuel homeostasis during fasting. A and B: RPMI-1640 vehicle – or C75-treated male mice were fasted for 24 h and examined for PDC activity in skeletal muscle (A) and blood glucose levels (B). C and D: Measurements of oxygen consumption (C) and RQ (D) during fasting were carried out in the metabolic cage during fasting. All data shown are means ± SEM; n = 4–6. *P < 0.05, **P < 0.01, ***P < 0.001 vs. wild-type (WT) mice.
Mentions: Because de novo fatty acid synthesis uses acetyl-CoA oxidized from pyruvate as substrate, we asked whether TLR4 controls PDC activity and blood glucose levels through fatty acid synthesis regulation. As expected, we found that C75 treatment abolished the increase in muscle PDC activity and the severe fasting hypoglycemia resulting from TLR4 deficiency (Fig. 6A and 6B). These findings indicate that excess acetyl-CoA from increased muscle pyruvate oxidative decarboxylation in TLR4−/− mice may enter lipogenesis instead of TCA cycle. Thus, to better understand the effect of TLR4 deficiency on systemic fuel utilization, energy expenditure and respiratory quotient (RQ) were determined. During fasting, total energy expenditure was comparable in TLR4−/− mice and wild-type mice (Fig. 6C). The RQ of wild-type and TLR4−/− mice exhibited a similar pattern, with a rapid decrease after fasting followed by a steady level, indicating the shift of fuel utilization from carbohydrates to fat. However, the RQ of TLR4−/− mice decreased to a lower level than that of wild-type mice (Fig. 6D), indicating that more fat was used as energy. The lower RQ level in TLR4−/− mice is consistent with their increased FAO rates and supports that the products of pyruvate oxidative decarboxylation may be used for lipogenesis. Collectively, these data suggest an important role for TLR4 in maintaining the homeostasis between glucose and lipid fuel during fasting.

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