Disruption of inducible 6-phosphofructo-2-kinase impairs the suppressive effect of PPARγ activation on diet-induced intestine inflammatory response

• Published in: The Journal of nutritional biochemistry Vol. 24; no. 5; pp. 770 - 775
• Main Authors: Guo, Xin, Li, Honggui, Xu, Hang, Halim, Vera, Thomas, Laura N, Woo, Shih-Lung, Huo, Yuqing, Chen, Y. Eugene, Sturino, Joseph M, Wu, Chaodong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2013
• Subjects: 6-phosphofructo-2-kinase; Adipocytes - enzymology; adipose tissue; Adipose Tissue - metabolism; agonists; Animals; Bifidobacterium - isolation & purification; Blotting, Western; Diet, Fat-Restricted; Diet, High-Fat - adverse effects; genes; Glycolysis; high fat diet; Hypoglycemic Agents - pharmacology; Inducible 6-phosphofructo-2-kinase; inflammation; Inflammation - metabolism; Inflammatory response; Insulin Resistance; Intestine; Intestines - enzymology; Intestines - microbiology; Lactobacillus - isolation & purification; low fat diet; Male; Mice; Mice, Inbred C57BL; mitogen-activated protein kinase; Mitogen-Activated Protein Kinase 8 - genetics; Mitogen-Activated Protein Kinase 8 - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; Overnutrition; Phosphofructokinase-2 - antagonists & inhibitors; Phosphofructokinase-2 - genetics; Phosphofructokinase-2 - metabolism; Phosphorylation; PPAR gamma - agonists; PPAR gamma - genetics; PPAR gamma - metabolism; PPARγ; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Thiazolidinediones - pharmacology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Inflammatory response; Intestine; Inducible 6-phosphofructo-2-kinase; PPARγ; Overnutrition
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2012.04.007

PFKFB3 is a target gene of peroxisome proliferator-activated receptor gamma (PPARγ) and encodes for inducible 6-phosphofructo-2-kinase (iPFK2). As a key regulatory enzyme that stimulates glycolysis, PFKFB3/iPFK2 links adipocyte metabolic and inflammatory responses. Additionally, PFKFB3/iPFK2 is involved in the effect of active PPARγ on suppressing overnutrition-induced adipose tissue inflammatory response, which accounts for the insulin-sensitizing and antidiabetic effects of PPARγ activation. Using PFKFB3/iPFK2-disrupted mice, the present study investigated the role of PFKFB3/iPFK2 in regulating overnutrition-associated intestine inflammatory response and in mediating the effects of PPARγ activation. In wild-type mice, intestine PFKFB3/iPFK2 was increased in response to high-fat diet (HFD) feeding compared with that in mice fed a low-fat diet. However, intestine PFKFB3/iPFK2 was decreased in PFKFB3/iPFK2-disrupted mice and did not respond to HFD feeding. Furthermore, on an HFD, PFKFB3/iPFK2-disrupted mice displayed a significant increase in major intestine proinflammatory indicators such as toll-like receptor 4 expression, c-Jun N-terminal kinase 1 and nuclear factor kappa B phosphorylation, and proinflammatory cytokine expression compared with wild-type littermates. Upon treatment with rosiglitazone, an agonist of PPARγ, intestine proinflammatory indicators were markedly decreased in wild-type mice, but to a much lesser degree in PFKFB3/iPFK2-disrupted mice. Overall, the status of HFD-induced intestine inflammatory response in all treated mice correlated inversely with systemic insulin sensitivity, indicated by the homeostasis model assessment of insulin resistance data. Together, these results suggest that PFKFB3/iPFK2 is critically involved in the effect of PPARγ activation on suppressing diet-induced intestine inflammatory response.