MAP3K8 (TPL2/COT) affects obesity-induced adipose tissue inflammation without systemic effects in humans and in mice

PLoS One. 2014 Feb 24;9(2):e89615. doi: 10.1371/journal.pone.0089615.

Dov B Ballak ¹, Peter van Essen ², Janna A van Diepen ², Henry Jansen ³, Anneke Hijmans ³, Tetsuya Matsuguchi ⁴, Helmut Sparrer ⁵, Cees J Tack ³, Mihai G Netea ⁶, Leo A B Joosten ⁶, Rinke Stienstra ⁷

Affiliations

1 Department of Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands ; Institute for Genomic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands ; Nijmegen Institute for Infection Inflammation and Immunity, Radboud University Medical Centre, Nijmegen, The Netherlands.
2 Department of Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands ; Institute for Genomic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
3 Department of Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
4 Department of Oral Biochemistry, Field of Developmental Medicine, Kagoshima University, Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima, Japan.
5 Novartis Pharma AG, Basel, Switzerland.
6 Department of Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands ; Nijmegen Institute for Infection Inflammation and Immunity, Radboud University Medical Centre, Nijmegen, The Netherlands.
7 Department of Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands ; Institute for Genomic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands ; Department of Human Nutrition, Wageningen University and Research Centre, Wageningen, The Netherlands.

PMID: 24586913 DOI: 10.1371/journal.pone.0089615

Abstract

Chronic low-grade inflammation in adipose tissue often accompanies obesity, leading to Insulin resistance and increasing the risk for metabolic diseases. MAP3K8 (TPL2/COT) is an important signal transductor and activator of pro-inflammatory pathways that has been linked to obesity-induced adipose tissue inflammation. We used human adipose tissue biopsies to study the relationship of MAP3K8 expression with markers of obesity and expression of pro-inflammatory cytokines (IL-1β, IL-6 and IL-8). Moreover, we evaluated obesity-induced adipose tissue inflammation and Insulin resistance in mice lacking MAP3K8 and WT mice on a high-fat diet (HFD) for 16 weeks. Individuals with a BMI >30 displayed a higher mRNA expression of MAP3K8 in adipose tissue compared to individuals with a normal BMI. Additionally, high mRNA expression levels of IL-1β, IL-6 and IL-8, but not TNF -α, in human adipose tissue were associated with higher expression of MAP3K8. Moreover, high plasma SAA and CRP did not associate with increased MAP3K8 expression in adipose tissue. Similarly, no association was found for MAP3K8 expression with plasma Insulin or glucose levels. Mice lacking MAP3K8 had similar bodyweight gain as WT mice, yet displayed lower mRNA expression levels of IL-1β, IL-6 and CXCL1 in adipose tissue in response to the HFD as compared to WT Animals. However, MAP3K8 deficient mice were not protected against HFD-induced adipose tissue macrophage infiltration or the development of Insulin resistance. Together, the data in both human and mouse show that MAP3K8 is involved in local adipose tissue inflammation, specifically for IL-1β and its responsive cytokines IL-6 and IL-8, but does not seem to have systemic effects on Insulin resistance.

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