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United States Department of Agriculture

Agricultural Research Service

Research Project: REGULATION OF ADIPOCYTE AND ADIPOSE TISSUE METABOLISM IN OBESITY RELATED INFLAMMATION AND METABOLIC DISORDERS Title: Tumor progression locus 2 (TPL2) regulates obesity-associated inflammation and insulin resistance

Authors
item Perfield, James -
item Lee, Yunkyoung -
item Shulman, Gerald -
item Samuel, Varman -
item Jurczak, Michael -
item Chang, Eugene -
item Tsichilis, Philip -
item Obin, Martin -
item Greenberg, Andrew -

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 24, 2011
Publication Date: April 1, 2011
Citation: Perfield, J.W., Lee, Y., Shulman, G.I., Samuel, V.T., Jurczak, M.J., Chang, E., Tsichilis, P.N., Obin, M.S., Greenberg, A.S. 2011. Tumor progression locus 2 (TPL2) regulates obesity-associated inflammation and insulin resistance. Diabetes. 60(4):1168-1176.

Interpretive Summary: Obesity induces low-grade systemic inflammation resulting from increased adipose mass. It is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated that the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2) is one of the inflammatory signaling regulators that is upregulated in the obese state. We employed TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance. Male TPL2KO and Wild-type (WT) littermates were fed either a low fat diet or a high fat diet to investigate the effect of TPL2 deletion on obesity, inflammation, and insulin sensitivity. We demonstrated that TPL2 deletion does not alter body weight gain or adipose depot weight although their insulin sensitivity was improved compared to the obese WT mice. Consistent with an improved metabolic phenotype, immune cell infiltration and inflammation was attenuated in the adipose tissue of obese TPL2KO mice that were coincident with reduced hepatic inflammatory gene expression and lipid accumulation. Taken together, our results provide the first in vivo demonstration that TPL2 promotes obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity.

Technical Abstract: Obesity-associated low-grade systemic inflammation resulting from increased adipose mass is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2) is a regulator of inflammatory cytokine production that is upregulated in the obese state. We employed TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance. Male TPL2KO and Wild-type (WT) littermates were fed either a low fat diet or a high fat diet to investigate the effect of TPL2 deletion on obesity, inflammation and insulin sensitivity. We demonstrated that TPL2 deletion does not alter body weight gain or adipose depot weight. However, hyperinsulinemic euglycemic clamp studies revealed improved insulin sensitivity in obese TPL2KO mice relative to obese WT mice. Consistent with an improved metabolic phenotype, immune cell infiltration and inflammation was attenuated in the adipose tissue of obese TPL2KO mice coincident with reduced hepatic inflammatory gene expression and lipid accumulation. Our results provide the first in vivo demonstration that TPL2 promotes obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity.

Last Modified: 12/19/2014