Disruption of inducible 6-phosphofructo-2-kinase ameliorates diet-induced adiposity but exacerbates systemic insulin resistance and adipose tissue inflammatory response.
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.
Huo
Yuqing
Y
From the Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455. Electronic address: yuqing@umn.edu.
Guo
Xin
X
the Intercollegiate Faculty of Nutrition, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Li
Honggui
H
the Intercollegiate Faculty of Nutrition, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Wang
Huan
H
From the Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455.
Zhang
Weiyu
W
From the Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455.
Wang
Ying
Y
the Intercollegiate Faculty of Genetics, Department of Poultry Science, Texas A&M University, College Station, Texas 77843.
Zhou
Huaijun
H
the Intercollegiate Faculty of Genetics, Department of Poultry Science, Texas A&M University, College Station, Texas 77843.
Gao
Zhanguo
Z
the Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808.
Telang
Sucheta
S
the J. G. Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, and.
Chesney
Jason
J
the J. G. Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202, and.
Chen
Y Eugene
YE
the Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48105.
Ye
Jianping
J
the Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808.
Chapkin
Robert S
RS
the Intercollegiate Faculty of Nutrition, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843.
Wu
Chaodong
C
the Intercollegiate Faculty of Nutrition, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas 77843. Electronic address: cdwu@tamu.edu.
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D015153:Blotting, Western; D004041:Dietary Fats / Q000008:administration & dosage*; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D004041:Dietary Fats; D018836:Inflammation Mediators; D007328:Insulin; D015850:Interleukin-6; D020738:Leptin; D047493:PPAR alpha; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D025481:Phosphofructokinase-2