Objective Obesity-associated metabolic dysfunction increases the risk of multiple diseases such as type 2 diabetes and cardiovascular disease. The importance of the co-stimulatory CD40-CD40L dyad in diet-induced obesity (DIO), with opposing phenotypes arising when either the receptor (aggravating) or the ligand (protective) is deleted, has been described previously. The functions of CD40 and CD40L are cell type dependent. As co-stimulation via T cell-mediated CD40L is essential for driving inflammation, we here investigate the role of T cell CD40L in DIO.
Research design and methods CD4CreCD40Lfl/fl mice on a C57BL/6 background were generated and subjected to DIO by administration of 15 weeks of high fat diet (HFD).
Results HFD-fed CD4CreCD40Lfl/fl mice had similar weight gain, adipocyte sizes, plasma cholesterol and triglyceride levels as their wild-type (WT) counterparts. Insulin and glucose tolerance were comparable, although CD4CreCD40Lfl/fl mice did have a decreased plasma insulin concentration, suggesting a minor improvement of insulin resistance. Furthermore, although the degree of hepatosteatosis was similar in both genotypes, the gene expression of fatty acid synthase 1 and ATP-citrate lyase had decreased, whereas expression of peroxisome proliferator-activated receptor-α had increased in livers of CD4CreCD40Lfl/fl mice, suggesting decreased hepatic lipid uptake in absence of T cell CD40L.
Moreover, CD4CreCD40Lfl/fl mice displayed significantly lower numbers of effector memory CD4+ T cells and regulatory T cells in blood and lymphoid organs compared with WT. However, immune cell composition and inflammatory status of the adipose tissue was similar in CD4CreCD40Lfl/fl and WT mice.
Conclusions T cell CD40L deficiency results in a minor improvement of insulin sensitivity and hepatic steatosis in DIO, despite the strong decrease in effector T cells and regulatory T cells in blood and lymphoid organs. Our data indicate that other CD40L-expressing cell types are more relevant in the pathogenesis of obesity-associated metabolic dysfunction.
- type 2 diabetes
- T cells
- T lymphocyte activation
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SABMA and EL contributed equally.
Contributors The study presented here was carried out in collaboration among all authors. MER contributed to concept and design, experiments and procedures, analysis and interpretation of data, statistical analysis and drafting of the manuscript. MdT, LW, BvO and MJJG performed experiments and acquired data. NG contributed to concept and design, and critical revision of the manuscript. SABMA contributed to concept and design, experiments and procedures, interpretation of data and critical revision of the manuscript. EL contributed to concept and design, data interpretation, critical revision of the manuscript for important intellectual content and obtained funding.
Funding This work was financially supported by The Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands, Organization for Health Research and Development and the Royal Netherlands Academy of Sciences for the GENIUS-II project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis-II’ (CVON). This study was also supported by the Netherlands Organization for Scientific Research (NWO) (VICI grant 016.130.676 to EL), the EU (H2020-PHC-2015-667673, REPROGRAM to EL), the European Research Council (ERC consolidator grant CD40-INN 681492 to EL), the German Science Foundation (DFG, CRC1123, project A5).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All experimental procedures were approved by the Ethical Committee for Animal Experiments of the Amsterdam UMC animal permit number (AVD1180020171666).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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