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

Abstract

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.

• Authors: Xin Guo, Honggui Li, Hang Xu, Vera Halim, Laura N Thomas, Shih-Lung Woo, Yuqing Huo, Y Eugene Chen, Joseph M Sturino, Chaodong Wu
• Journal: The Journal of nutritional biochemistry (J Nutr Biochem) Vol. 24 Issue 5 Pg. 770-5 (May 2013) ISSN: 1873-4847 [Electronic] United States
• PMID: 22841546 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Hypoglycemic Agents
• NF-kappa B
• PPAR gamma
• RNA, Messenger
• Thiazolidinediones
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Rosiglitazone
• Phosphofructokinase-2
• Mitogen-Activated Protein Kinase 8

Topics

• Adipocytes (enzymology)
• Adipose Tissue (metabolism)
• Animals
• Bifidobacterium (isolation & purification)
• Blotting, Western
• Diet, Fat-Restricted
• Diet, High-Fat (adverse effects)
• Glycolysis
• Hypoglycemic Agents (pharmacology)
• Inflammation (metabolism)
• Insulin Resistance
• Intestines (enzymology, microbiology)
• Lactobacillus (isolation & purification)
• Male
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 8 (genetics, metabolism)
• NF-kappa B (genetics, metabolism)
• PPAR gamma (agonists, genetics, metabolism)
• Phosphofructokinase-2 (antagonists & inhibitors, genetics, metabolism)
• Phosphorylation
• RNA, Messenger (genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Rosiglitazone
• Thiazolidinediones (pharmacology)
• Toll-Like Receptor 4 (genetics, metabolism)