Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1

Endo, Yusuke; Asou, Hikari K.; Matsugae, Nao; Hirahara, Kiyoshi; Shinoda, Kenta; Tumes, Damon J.; Tokuyama, Hirotake; Yokote, Koutaro; Nakayama, Toshinori

doi:10.1016/j.celrep.2015.07.014

Cited by 192 publications

(208 citation statements)

References 55 publications

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“…Both pathways are required for the early and full activation and metabolic reprogramming of naive or memory CD4 + T cells in murine and human systems. Consistent with our findings, hyperlipidemia caused by obesity or atherogenic conditions exhibited an increased frequency of CD44 hi population among the CD4 + T cells4045. Highly proliferating cells including activated T cells appear to require large amounts of fatty acids.…”

Section: Discussionsupporting

confidence: 90%

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Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells

et al. 2016

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To fulfil the bioenergetic requirements for increased cell size and clonal expansion, activated T cells reprogramme their metabolic signatures from energetically quiescent to activated. However, the molecular mechanisms and essential components controlling metabolic reprogramming in T cells are not well understood. Here, we show that the mTORC1–PPARγ pathway is crucial for the fatty acid uptake programme in activated CD4+ T cells. This pathway is required for full activation and rapid proliferation of naive and memory CD4+ T cells. PPARγ directly binds and induces genes associated with fatty acid uptake in CD4+ T cells in both mice and humans. The PPARγ-dependent fatty acid uptake programme is critical for metabolic reprogramming. Thus, we provide important mechanistic insights into the metabolic reprogramming mechanisms that govern the expression of key enzymes, fatty acid metabolism and the acquisition of an activated phenotype during CD4+ T cell activation.

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Section: Discussionsupporting

confidence: 90%

“…We previously reported that extrinsic fatty acid supplementation restored the function of Acaca −/− Th17 cells40. Those data led us to postulate that cellular fatty acid was limiting in TOFA-treated or GW9662-treated CD4 + T cells in the early activation phase.…”

Section: Resultsmentioning

confidence: 92%

Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells

et al. 2016

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“…We also show that the frequency of IL‐23R expressing T helper cells is increased by combined hypercholesterolemia and hyperlipidemia, a finding consistent with increased Th17 generation in hyperlipidemic mice 14. Focusing on CD4 + T cells, IL‐23R expression was found to be largely restricted to CCR6 + cells with an effector memory (CD44 hi CD62 low ) phenotype that is consistent with IL‐23R expressed in antigen‐experienced Th17 cells 15…”

Section: Discussionsupporting

confidence: 68%

IL‐23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice

Engelbertsen

Depuydt

Verwilligen

et al. 2018

JAHA

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BackgroundInterleukin‐23 (IL‐23) has been implicated in inflammatory and autoimmune diseases by skewing CD4+ T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL‐23 receptor (IL‐23R)‐expressing cells in the atherosclerotic aorta and evaluated the effect of IL‐23R deficiency on atherosclerosis development in mice.Methods and ResultsWe used heterozygous Ldlr −/− Il23r e GFP / WT knock‐in mice to identify IL‐23R‐expressing cells by flow cytometry and homozygous Ldlr −/− Il23r e GFP / eGFP (Ldlr −/− Il23r −/−) mice to investigate the effect of lack of IL‐23R in atherosclerosis. We demonstrate the presence of relatively rare IL‐23R‐expressing cells in lymphoid tissue and aorta (≈0.1–1% IL23R+ cells of all CD45+ leukocytes). After 10 weeks on a high‐fat diet, production of IL‐17, but not interferon‐γ, by CD4+ T cells and other lymphocytes was reduced in Ldlr −/− Il23r −/− compared with Ldlr −/−controls. However, Ldlr −/− and Ldlr −/− Il23r −/− mice had equivalent amounts of aortic sinus and descending aorta lesions. Adoptive transfer of IL‐23R‐deficient CD4+ T cells to lymphopenic Ldlr −/− Rag1 −/− resulted in dramatically reduced IL‐17‐producing T cells but did not reduce atherosclerosis, compared with transfer of IL‐23R‐sufficient CD4+ T cells.ConclusionsThese data demonstrate that loss of IL‐23R does not affect development of experimental atherosclerosis in LDLr‐deficient mice, despite a role for IL‐23 in differentiation of IL‐17‐producing T cells.

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“…RORC (RAR-Related Orphan Receptor C) regulates production of the inflammatory cytokine IL-17 by T helper-17 (Th17) cells; Th17 cell activation and cytokine production appears to play a critical role in the pathogenesis of diabetes (37-41). Additionally, genetic variation in RORC has been linked to body fat composition levels in cattle (42).…”

Section: Discussionmentioning

confidence: 99%

An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort

Wilson

Harlid

et al. 2016

Int J Obes

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Background/Objectives The relationship between obesity and chronic disease risk is well-established; the underlying biological mechanisms driving this risk increase may include obesity-related epigenetic modifications. To explore this hypothesis, we conducted a genome-wide analysis of DNA methylation and body mass index (BMI) using data from a subset of women in the Sister Study. Subjects/Methods The Sister Study is a cohort of 50,884 U.S. women who had a sister with breast cancer but were free of breast cancer themselves at enrollment. Study participants completed examinations which included measurements of height and weight, and provided blood samples. Blood DNA methylation data generated with the Illumina Infinium HumanMethylation27 BeadChip array covering 27,589 CpG sites was available for 871 women from a prior study of breast cancer and DNA methylation. To identify differentially methylated CpG sites associated with body mass index, we analyzed this methylation data using robust linear regression with adjustment for age and case status. For those CpGs passing the false discovery rate significance level, we examined the association in a replication set comprised of a non-overlapping group of 187 women from the Sister Study who had DNA methylation data generated using the Infinium HumanMethylation450 BeadChip array. Analysis of this expanded 450K array identified additional BMI-associated sites which were investigated with targeted pyrosequencing. Results Four CpG sites reached genome-wide significance (FDR q<0.05) in the discovery set and associations for all four were significant at strict Bonferroni correction in the replication set. An additional 23 sites passed FDR in the replication set and 5 were replicated by pyrosequencing in the discovery set. Several of the genes identified including ANGPT4, RORC, SOCS3, FSD2, XYLT1, ABCG1, STK39, ASB2, and CRHR2 have been linked to obesity and obesity-related chronic diseases. Conclusions Our findings support the hypothesis that obesity-related epigenetic differences are detectable in blood and may be related to risk of chronic disease.

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Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1

Cited by 192 publications

References 55 publications

Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells

Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells

IL‐23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice

An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort

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