Targeted overexpression of inducible 6-phosphofructo-2-kinase in adipose tissue increases fat deposition but protects against diet-induced insulin resistance and inflammatory responses

Yuqing Huo, Xin Guo, Honggui Li, Hang Xu, Vera Halim, Weiyu Zhang, Huan Wang, Yang Yi Fan, Kuok Teong Ong, Shih Lung Woo, Robert S. Chapkin, Douglas G. Mashek, Yanming Chen, Hui Dong, Fuer Lu, Lai Wei, Chaodong Wu

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33 Scopus citations

Abstract

Increasing evidence demonstrates the dissociation of fat deposition, the inflammatory response, and insulin resistance in the development of obesity-related metabolic diseases. As a regulatory enzyme of glycolysis, inducible 6-phosphofructo-2-kinase (iPFK2, encoded by PFKFB3) protects against diet-induced adipose tissue inflammatory response and systemic insulin resistance independently of adiposity. Using aP2-PFKFB3 transgenic (Tg) mice, we explored the ability of targeted adipocyte PFKFB3/iPFK2 overexpression to modulate diet-induced inflammatory responses and insulin resistance arising from fat deposition in both adipose and liver tissues. Compared with wild-type littermates (controls) on a high fat diet (HFD), Tg mice exhibited increased adiposity, decreased adipose inflammatory response, and improved insulin sensitivity. In a parallel pattern, HFD-fed Tg mice showed increased hepatic steatosis, decreased liver inflammatory response, and improved liver insulin sensitivity compared with controls. In both adipose and liver tissues, increased fat deposition was associated with lipid profile alterations characterized by an increase in palmitoleate. Additionally, plasma lipid profiles also displayed an increase in palmitoleate in HFD-Tg mice compared with controls. In cultured 3T3-L1 adipocytes, overexpression of PFKFB3/iPFK2 recapitulated metabolic and inflammatory changes observed in adipose tissue of Tg mice. Upon treatment with conditioned medium from iPFK2-overexpressing adipocytes, mouse primary hepatocytes displayed metabolic and inflammatory responses that were similar to those observed in livers of Tg mice. Together, these data demonstrate a unique role for PFKFB3/iPFK2 in adipocytes with regard to diet-induced inflammatory responses in both adipose and liver tissues.

Original languageEnglish (US)
Pages (from-to)21492-21500
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number25
DOIs
StatePublished - Jun 15 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Huo, Y., Guo, X., Li, H., Xu, H., Halim, V., Zhang, W., Wang, H., Fan, Y. Y., Ong, K. T., Woo, S. L., Chapkin, R. S., Mashek, D. G., Chen, Y., Dong, H., Lu, F., Wei, L., & Wu, C. (2012). Targeted overexpression of inducible 6-phosphofructo-2-kinase in adipose tissue increases fat deposition but protects against diet-induced insulin resistance and inflammatory responses. Journal of Biological Chemistry, 287(25), 21492-21500. https://doi.org/10.1074/jbc.M112.370379