ARS | Publication request: Tumor progression locus 2 (TPL2) is a novel target for regulating obesity associated liver inflammation and steatosis

Submitted to: Experimental Biology
Publication Type: Abstract Only
Publication Acceptance Date: December 1, 2007
Publication Date: April 5, 2008
Repository URL: http://www.fasebj.org/cgi/content/meeting_abstract/22/1_MeetingAbstracts/1037.7
Citation: Perfield, J.W., Tsichlis, P.N., Greenberg, A.S. 2008. Tumor progression locus 2 (TPL2) is a novel target for regulating obesity associated liver inflammation and steatosis. Experimental Biology. 22:1037.7.

Technical Abstract: Tumor progression locus 2 (TPL2) is a MAP 3-kinase that is required for toll receptor and tumor necrosis factor-alpha (TNF-alpha) stimulation of the ERK/MAP kinase cascade. TPL-2 knockout (KO) mice exhibit a dramatic reduction in LPS induced TNF-alpha production due to defective ERK-1/2 activation. TNF-alpha 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-alpha, IL-6, and IL-1beta 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.