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Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction
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)...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936585/ https://www.ncbi.nlm.nih.gov/pubmed/31908798 http://dx.doi.org/10.1136/bmjdrc-2019-000829 |
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author | Reiche, Myrthe E den Toom, Myrthe Willemsen, Lisa van Os, Bram Gijbels, Marion J J Gerdes, Norbert Aarts, Suzanne A B M Lutgens, Esther |
author_facet | Reiche, Myrthe E den Toom, Myrthe Willemsen, Lisa van Os, Bram Gijbels, Marion J J Gerdes, Norbert Aarts, Suzanne A B M Lutgens, Esther |
author_sort | Reiche, Myrthe E |
collection | PubMed |
description | 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: CD4CreCD40L(fl/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 CD4CreCD40L(fl/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 CD4CreCD40L(fl/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 CD4CreCD40L(fl/fl) mice, suggesting decreased hepatic lipid uptake in absence of T cell CD40L. Moreover, CD4CreCD40L(fl/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 CD4CreCD40L(fl/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. |
format | Online Article Text |
id | pubmed-6936585 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-69365852020-01-06 Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction Reiche, Myrthe E den Toom, Myrthe Willemsen, Lisa van Os, Bram Gijbels, Marion J J Gerdes, Norbert Aarts, Suzanne A B M Lutgens, Esther BMJ Open Diabetes Res Care Obesity Studies 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: CD4CreCD40L(fl/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 CD4CreCD40L(fl/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 CD4CreCD40L(fl/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 CD4CreCD40L(fl/fl) mice, suggesting decreased hepatic lipid uptake in absence of T cell CD40L. Moreover, CD4CreCD40L(fl/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 CD4CreCD40L(fl/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. BMJ Publishing Group 2019-12-17 /pmc/articles/PMC6936585/ /pubmed/31908798 http://dx.doi.org/10.1136/bmjdrc-2019-000829 Text en © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Obesity Studies Reiche, Myrthe E den Toom, Myrthe Willemsen, Lisa van Os, Bram Gijbels, Marion J J Gerdes, Norbert Aarts, Suzanne A B M Lutgens, Esther Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction |
title | Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction |
title_full | Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction |
title_fullStr | Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction |
title_full_unstemmed | Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction |
title_short | Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction |
title_sort | deficiency of t cell cd40l has minor beneficial effects on obesity-induced metabolic dysfunction |
topic | Obesity Studies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936585/ https://www.ncbi.nlm.nih.gov/pubmed/31908798 http://dx.doi.org/10.1136/bmjdrc-2019-000829 |
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