Article

Diabetologia

, Volume 53, Issue 8, pp 1795-1806

Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet

  • J. A. EhsesAffiliated withDepartment of Surgery, Faculty of Medicine, University of British Columbia, Child & Family Research Institute Email author 
  • , D. T. MeierAffiliated withDivision of Endocrinology, Diabetes, & Nutrition, University Hospital of ZurichZurich Centre for Integrative Human Physiology, University of Zurich
  • , S. WueestAffiliated withZurich Centre for Integrative Human Physiology, University of ZurichDivision of Paediatric Endocrinology and Diabetology, University Children’s Hospital
  • , J. RytkaAffiliated withZurich Centre for Integrative Human Physiology, University of ZurichDivision of Paediatric Endocrinology and Diabetology, University Children’s Hospital
  • , S. BollerAffiliated withDivision of Endocrinology, Diabetes, & Nutrition, University Hospital of ZurichZurich Centre for Integrative Human Physiology, University of Zurich
  • , P. Y. WielingaAffiliated withInstitute of Veterinary Physiology, and Zurich Centre for Integrative Human Physiology, Vetsuisse Faculty University of Zurich
  • , A. SchraenenAffiliated withDepartment of Molecular Cell Biology, Gene Expression Unit, Katholieke Universiteit Leuven
  • , K. LemaireAffiliated withDepartment of Molecular Cell Biology, Gene Expression Unit, Katholieke Universiteit Leuven
  • , S. DebrayAffiliated withDepartment of Molecular Cell Biology, Gene Expression Unit, Katholieke Universiteit Leuven
    • , L. Van LommelAffiliated withDepartment of Molecular Cell Biology, Gene Expression Unit, Katholieke Universiteit Leuven
    • , J. A. PospisilikAffiliated withInstitute of Molecular Biotechnology of the Austrian Academy of Science
    • , O. TschoppAffiliated withDivision of Endocrinology, Diabetes, & Nutrition, University Hospital of Zurich
    • , S. M. SchultzeAffiliated withDivision of Endocrinology, Diabetes, & Nutrition, University Hospital of Zurich
    • , U. MalipieroAffiliated withDivision of Clinical Immunology, University Hospital of Zurich
    • , H. EsterbauerAffiliated withDepartment of Medical and Chemical Laboratory Diagnostics, Medical University Vienna
    • , H. EllingsgaardAffiliated withDivision of Endocrinology, Diabetes, & Nutrition, University Hospital of ZurichZurich Centre for Integrative Human Physiology, University of Zurich
    • , S. RüttiAffiliated withDivision of Endocrinology, Diabetes, & Nutrition, University Hospital of ZurichZurich Centre for Integrative Human Physiology, University of Zurich
    • , F. C. SchuitAffiliated withDepartment of Molecular Cell Biology, Gene Expression Unit, Katholieke Universiteit Leuven
    • , T. A. LutzAffiliated withInstitute of Veterinary Physiology, and Zurich Centre for Integrative Human Physiology, Vetsuisse Faculty University of Zurich
    • , M. Böni-SchnetzlerAffiliated withDivision of Endocrinology, Diabetes, & Nutrition, University Hospital of ZurichZurich Centre for Integrative Human Physiology, University of Zurich
    • , D. KonradAffiliated withZurich Centre for Integrative Human Physiology, University of ZurichDivision of Paediatric Endocrinology and Diabetology, University Children’s Hospital
    • , Marc Y. DonathAffiliated withDivision of Endocrinology, Diabetes, & Nutrition, University Hospital of ZurichZurich Centre for Integrative Human Physiology, University of Zurich

Abstract

Aims/hypothesis

Inflammation contributes to both insulin resistance and pancreatic beta cell failure in human type 2 diabetes. Toll-like receptors (TLRs) are highly conserved pattern recognition receptors that coordinate the innate inflammatory response to numerous substances, including NEFAs. Here we investigated a potential contribution of TLR2 to the metabolic dysregulation induced by high-fat diet (HFD) feeding in mice.

Methods

Male and female littermate Tlr2 +/+ and Tlr2 −/− mice were analysed with respect to glucose tolerance, insulin sensitivity, insulin secretion and energy metabolism on chow and HFD. Adipose, liver, muscle and islet pathology and inflammation were examined using molecular approaches. Macrophages and dendritic immune cells, in addition to pancreatic islets were investigated in vitro with respect to NEFA-induced cytokine production.

Results

While not showing any differences in glucose homeostasis on chow diet, both male and female Tlr2 −/− mice were protected from the adverse effects of HFD compared with Tlr2 +/+ littermate controls. Female Tlr2 −/− mice showed pronounced improvements in glucose tolerance, insulin sensitivity, and insulin secretion following 20 weeks of HFD feeding. These effects were associated with an increased capacity of Tlr2 −/− mice to preferentially burn fat, combined with reduced tissue inflammation. Bone-marrow-derived dendritic cells and pancreatic islets from Tlr2 −/− mice did not increase IL-1β expression in response to a NEFA mixture, whereas Tlr2 +/+ control tissues did.

Conclusion/interpretation

These data suggest that TLR2 is a molecular link between increased dietary lipid intake and the regulation of glucose homeostasis, via regulation of energy substrate utilisation and tissue inflammation.

Keywords

Diabetes Insulin resistance IL-1 Pancreatic islet Toll like receptor 2