Tumor Progression Locus 2 (TPL2) Regulates Obesity-Associated Inflammation and Insulin Resistance

  1. Andrew S. Greenberg1
  1. 1Obesity and Metabolism Laboratory, JM-USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts
  2. 2Howard Hughes Medical Institute, Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut
  3. 3West Haven VAMC, West Haven, Connecticut
  4. 4Molecular Oncology Research Institute, Tufts University School of Medicine, Boston, Massachusetts
  1. Corresponding author: Andrew S. Greenberg, andrew.greenberg{at}tufts.edu, or Martin S. Obin, martin.obin{at}tufts.edu.
  1. J.W.P. and Y.L. contributed equally to this study.

Abstract

OBJECTIVE 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 that the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2), a kinase that integrates signals from Toll receptors, cytokine receptors, and inhibitor of κ-B kinase-β is an important regulator of inflammatory pathways. We used TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance.

RESEARCH DESIGN AND METHODS Male TPL2KO and wild-type (WT) littermates were fed a low-fat diet or a high-fat diet to investigate the effect of TPL2 deletion on obesity, inflammation, and insulin sensitivity.

RESULTS We demonstrate that TPL2 deletion does not alter body weight gain or adipose depot weight. However, hyperinsulinemic euglycemic clamp studies revealed improved insulin sensitivity with enhanced glucose uptake in skeletal muscle and increased suppression of hepatic glucose output in obese TPL2KO mice compared with 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.

CONCLUSIONS Our results provide the first in vivo demonstration that TPL2 ablation attenuates obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity.

Footnotes

  • Received May 19, 2010.
  • Accepted January 24, 2011.

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  1. Diabetes vol. 60 no. 4 1168-1176
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