Involvement of inducible 6-phosphofructo-2-kinase in the anti-diabetic effect of peroxisome proliferator-activated receptor γ activation in mice

Xin Guo, Kefeng Xu, Jifeng Zhang, Honggui Li, Weiyu Zhang, Huan Wang, Alex J. Lange, Y. Eugene Chen, Yuqing Huo, Chaodong Wu

Research output: Contribution to journalArticle

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Abstract

PFKFB3 is the gene that codes for the inducible isoform of 6-phosphofructo-2-kinase (iPFK2), a key regulatory enzyme of glycolysis. As one of the targets of peroxisome proliferator-activated receptor γ (PPARγ), PFKFB3/iPFK2 is up-regulated by thiazolidinediones. In the present study, using PFKFB3/iPFK2-disrupted mice, the role of PFKFB3/iPFK2 in the anti-diabetic effect of PPARγactivation was determined. In wild-type littermate mice, PPARγactivation (i.e. treatment with rosiglitazone) restored euglycemia and reversed high fat diet-induced insulin resistance and glucose intolerance. In contrast, PPARγ activation did not reduce high fat diet-induced hyperglycemia and failed to reverse insulin resistance and glucose intolerance in PFKFB3+/- mice. The lack of anti-diabetic effect in PFKFB3+/- mice was associated with the inability of PPARγ activation to suppress adipose tissue lipolysis and proinflammatory cytokine production, stimulate visceral fat accumulation, enhance adipose tissue insulin signaling, and appropriately regulate adipokine expression. Similarly, in cultured 3T3-L1 adipocytes, knockdown of PFKFB3/iPFK2 lessened the effect of PPARγactivation on stimulating lipid accumulation. Furthermore, PPARγ activation did not suppress inflammatory signaling in PFKFB3/iPFK2-knockdown adipocytes as it did in control adipocytes. Upon inhibition of excessive fatty acid oxidation in PFKFB3/iPFK2-knockdown adipocytes, PPARγ activation was able to significantly reverse inflammatory signaling and proinflammatory cytokine expression and restore insulin signaling. Together, these data demonstrate that PFKFB3/iPFK2 is critically involved in the anti-diabetic effect of PPARγ activation.

Original languageEnglish (US)
Pages (from-to)23711-23720
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number31
DOIs
StatePublished - Jul 30 2010

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Phosphofructokinase-2
Peroxisome Proliferator-Activated Receptors
Chemical activation
Adipocytes
Insulin
Glucose Intolerance
rosiglitazone
Fats
High Fat Diet
Nutrition
Insulin Resistance
Adipose Tissue
Tissue
Cytokines
Glucose
Thiazolidinediones
Adipokines
Intra-Abdominal Fat
Lipolysis
Glycolysis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Involvement of inducible 6-phosphofructo-2-kinase in the anti-diabetic effect of peroxisome proliferator-activated receptor γ activation in mice. / Guo, Xin; Xu, Kefeng; Zhang, Jifeng; Li, Honggui; Zhang, Weiyu; Wang, Huan; Lange, Alex J.; Chen, Y. Eugene; Huo, Yuqing; Wu, Chaodong.

In: Journal of Biological Chemistry, Vol. 285, No. 31, 30.07.2010, p. 23711-23720.

Research output: Contribution to journalArticle

Guo, Xin ; Xu, Kefeng ; Zhang, Jifeng ; Li, Honggui ; Zhang, Weiyu ; Wang, Huan ; Lange, Alex J. ; Chen, Y. Eugene ; Huo, Yuqing ; Wu, Chaodong. / Involvement of inducible 6-phosphofructo-2-kinase in the anti-diabetic effect of peroxisome proliferator-activated receptor γ activation in mice. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 31. pp. 23711-23720.
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abstract = "PFKFB3 is the gene that codes for the inducible isoform of 6-phosphofructo-2-kinase (iPFK2), a key regulatory enzyme of glycolysis. As one of the targets of peroxisome proliferator-activated receptor γ (PPARγ), PFKFB3/iPFK2 is up-regulated by thiazolidinediones. In the present study, using PFKFB3/iPFK2-disrupted mice, the role of PFKFB3/iPFK2 in the anti-diabetic effect of PPARγactivation was determined. In wild-type littermate mice, PPARγactivation (i.e. treatment with rosiglitazone) restored euglycemia and reversed high fat diet-induced insulin resistance and glucose intolerance. In contrast, PPARγ activation did not reduce high fat diet-induced hyperglycemia and failed to reverse insulin resistance and glucose intolerance in PFKFB3+/- mice. The lack of anti-diabetic effect in PFKFB3+/- mice was associated with the inability of PPARγ activation to suppress adipose tissue lipolysis and proinflammatory cytokine production, stimulate visceral fat accumulation, enhance adipose tissue insulin signaling, and appropriately regulate adipokine expression. Similarly, in cultured 3T3-L1 adipocytes, knockdown of PFKFB3/iPFK2 lessened the effect of PPARγactivation on stimulating lipid accumulation. Furthermore, PPARγ activation did not suppress inflammatory signaling in PFKFB3/iPFK2-knockdown adipocytes as it did in control adipocytes. Upon inhibition of excessive fatty acid oxidation in PFKFB3/iPFK2-knockdown adipocytes, PPARγ activation was able to significantly reverse inflammatory signaling and proinflammatory cytokine expression and restore insulin signaling. Together, these data demonstrate that PFKFB3/iPFK2 is critically involved in the anti-diabetic effect of PPARγ activation.",
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AU - Xu, Kefeng

AU - Zhang, Jifeng

AU - Li, Honggui

AU - Zhang, Weiyu

AU - Wang, Huan

AU - Lange, Alex J.

AU - Chen, Y. Eugene

AU - Huo, Yuqing

AU - Wu, Chaodong

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AB - PFKFB3 is the gene that codes for the inducible isoform of 6-phosphofructo-2-kinase (iPFK2), a key regulatory enzyme of glycolysis. As one of the targets of peroxisome proliferator-activated receptor γ (PPARγ), PFKFB3/iPFK2 is up-regulated by thiazolidinediones. In the present study, using PFKFB3/iPFK2-disrupted mice, the role of PFKFB3/iPFK2 in the anti-diabetic effect of PPARγactivation was determined. In wild-type littermate mice, PPARγactivation (i.e. treatment with rosiglitazone) restored euglycemia and reversed high fat diet-induced insulin resistance and glucose intolerance. In contrast, PPARγ activation did not reduce high fat diet-induced hyperglycemia and failed to reverse insulin resistance and glucose intolerance in PFKFB3+/- mice. The lack of anti-diabetic effect in PFKFB3+/- mice was associated with the inability of PPARγ activation to suppress adipose tissue lipolysis and proinflammatory cytokine production, stimulate visceral fat accumulation, enhance adipose tissue insulin signaling, and appropriately regulate adipokine expression. Similarly, in cultured 3T3-L1 adipocytes, knockdown of PFKFB3/iPFK2 lessened the effect of PPARγactivation on stimulating lipid accumulation. Furthermore, PPARγ activation did not suppress inflammatory signaling in PFKFB3/iPFK2-knockdown adipocytes as it did in control adipocytes. Upon inhibition of excessive fatty acid oxidation in PFKFB3/iPFK2-knockdown adipocytes, PPARγ activation was able to significantly reverse inflammatory signaling and proinflammatory cytokine expression and restore insulin signaling. Together, these data demonstrate that PFKFB3/iPFK2 is critically involved in the anti-diabetic effect of PPARγ activation.

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