title: Tumor progression locus 2 (TPL2) regulates obesity-associated inflammation and insulin resistance.
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.
  
  
  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.
authors.affiliation: Obesity and Metabolism Laboratory, JM-USDA Human Nutrition esearch Center on Aging, Tufts University, Boston, Massachusetts, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Perfield
authors.forename: Yunkyoung
authors.initials: Y
authors.lastname: Lee
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: Eugene
authors.initials: E
authors.lastname: Chang
authors.forename: Chen
authors.initials: C
authors.lastname: Xie
authors.forename: Phillip N
authors.initials: PN
authors.lastname: Tsichlis
authors.forename: Martin S
authors.initials: MS
authors.lastname: Obin
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
mesh_terms: D000273:Adipose Tissue / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D011518:Proto-Oncogene Proteins; D014280:Triglycerides; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse