Disruption of inducible 6-phosphofructo-2-kinase ameliorates diet-induced adiposity but exacerbates systemic insulin resistance and adipose tissue inflammatory response.

Abstract

Adiposity is commonly associated with adipose tissue dysfunction and many overnutrition-related metabolic diseases including type 2 diabetes. Much attention has been paid to reducing adiposity as a way to improve adipose tissue function and systemic insulin sensitivity. PFKFB3/iPFK2 is a master regulator of adipocyte nutrient metabolism. Using PFKFB3(+/-) mice, the present study investigated the role of PFKFB3/iPFK2 in regulating diet-induced adiposity and systemic insulin resistance. On a high-fat diet (HFD), PFKFB3(+/-) mice gained much less body weight than did wild-type littermates. This was attributed to a smaller increase in adiposity in PFKFB3(+/-) mice than in wild-type controls. However, HFD-induced systemic insulin resistance was more severe in PFKFB3(+/-) mice than in wild-type littermates. Compared with wild-type littermates, PFKFB3(+/-) mice exhibited increased severity of HFD-induced adipose tissue dysfunction, as evidenced by increased adipose tissue lipolysis, inappropriate adipokine expression, and decreased insulin signaling, as well as increased levels of proinflammatory cytokines in both isolated adipose tissue macrophages and adipocytes. In an in vitro system, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes caused a decrease in the rate of glucose incorporation into lipid but an increase in the production of reactive oxygen species. Furthermore, knockdown of PFKFB3/iPFK2 in 3T3-L1 adipocytes inappropriately altered the expression of adipokines, decreased insulin signaling, increased the phosphorylation states of JNK and NFkappaB p65, and enhanced the production of proinflammatory cytokines. Together, these data suggest that PFKFB3/iPFK2, although contributing to adiposity, protects against diet-induced insulin resistance and adipose tissue inflammatory response.

• Authors: Yuqing Huo, Xin Guo, Honggui Li, Huan Wang, Weiyu Zhang, Ying Wang, Huaijun Zhou, Zhanguo Gao, Sucheta Telang, Jason Chesney, Y Eugene Chen, Jianping Ye, Robert S Chapkin, Chaodong Wu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 6 Pg. 3713-3721 (Feb 05 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 19948719 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dietary Fats
• Inflammation Mediators
• Insulin
• Interleukin-6
• Leptin
• PPAR alpha
• Transcription Factors
• Tumor Necrosis Factor-alpha
• peroxisome-proliferator-activated receptor-gamma coactivator-1
• Phosphofructokinase-2

Topics

• 3T3-L1 Cells
• Adipocytes (cytology, metabolism)
• Adipose Tissue (drug effects, metabolism)
• Adiposity (drug effects)
• Animals
• Blotting, Western
• Dietary Fats (administration & dosage)
• Inflammation Mediators (metabolism)
• Insulin (blood)
• Insulin Resistance
• Interleukin-6 (genetics, metabolism)
• Leptin (blood)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• PPAR alpha (genetics, metabolism)
• Phosphofructokinase-2 (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Transcription Factors (genetics, metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)