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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. [ABSTRACT FROM AUTHOR]

The article discusses the results of the study "Circulating Triacylglycerol Signatures in Nonalcoholic Fatty Liver Disease Associated With the l148M Variant in PNPLA3 and With Obesity," by J. Hyysalo, P. Gopalacharyulu, H. Bian and colleagues, published within the issue. Findings show that patients expressing the variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) have lower circulating triacylglycerol (TAG) concentrations.