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Tumor progression locus 2 (TPL2) is a novel target for regulating obesity associated liver inflammation and steatosis
Author(s) -
Perfield James W,
Tsichlis Philip N,
Greenberg Andrew S
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1037.7
Subject(s) - steatosis , inflammation , lipogenesis , endocrinology , medicine , tumor necrosis factor alpha , fatty liver , biology , adipose tissue , disease
Tumor progression locus 2 (TPL2) is a MAP 3‐kinase that is required for toll receptor and tumor necrosis factor‐alpha (TNF‐α) stimulation of the ERK/MAP kinase cascade. TPL‐2 knockout (KO) mice exhibit a dramatic reduction in LPS induced TNF‐α production due to defective ERK‐1/2 activation. TNF‐α is increased in obesity, implicated in the upregulation of other inflammatory cytokines, and has been demonstrated to induce liver lipogenesis. The objective of this study was to determine if TPL2 is an important mediator of inflammation and liver steatosis associated with high fat feeding and obesity. Male wild‐type and TPL2KO mice were fed a high fat diet for 12 wks and the livers of these animals were investigated. TPL2KO mice were robustly protected from an increase in liver inflammation as mRNA expression of the inflammatory cytokines; TNF‐α, IL‐6, and IL‐1β were dramatically reduced by 60 to 80%. Despite no difference in body weight, TPL2KO mice tended to have smaller livers and decreased hepatic steatosis as determined by histological observation. In support of this observation, mRNA expression of lipogenic genes (FAS, ACC‐1, SREBP‐1c) was lower (>50%) in the livers of the TPL2KO mice. These data provide evidence that targeted disruption of TPL2 in the obese state results in decreased inflammation and hepatic steatosis. Ongoing studies will further define the role of TPL2 in mediating obesity associated inflammation. Supported in part by the Tufts‐NEMC Cancer Center Pilot Project Grant. USDA NIH