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Cited by 49Adipokines, Inflammation, and Metabolic DiseasesKruppel-like factors researchT-cell and B-cell Immunology

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KLF10 Deficiency in CD4+ T Cells Triggers Obesity, Insulin Resistance, and Fatty Liver

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Wara, Akm Khyrul, Wang, Shijia, Wu, Chun, Fang, Fang, Haemmig, Stefan, Weber, Brittany N., Aydogan, Ceren O., Tesmenitsky, Yevgenia, Aliakbarian, Hassan, Hawse, John R., Subramaniam, Malayannan, Zhao, Lei, Sage, Peter T., Tavakkoli, Ali, Garza, Amanda, Lynch, Lydia, Banks, Alexander S., Feinberg, Mark W.·2020·Cell Reports
DOI 10.1016/j.celrep.2020.108550PMC PMC7816773
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Abstract

CD4 + T cells regulate inflammation and metabolism in obesity. An imbalance of CD4 + T regulatory cells (Tregs) is critical in the development of insulin resistance and diabetes. Although cytokine control of this process is well understood, transcriptional regulation is not. KLF10, a member of the Kruppel-like transcription factor family, is an emerging regulator of immune cell function. We generated CD4 + -T-cell-specific KLF10 knockout (TKO) mice and identified a predisposition to obesity, insulin resistance, and fatty liver due to defects of CD4 + Treg mobilization to liver and adipose tissue depots and decreased transforming growth factor β3 (TGF-β3) release in vitro and in vivo . Adoptive transfer of wild-type CD4 + Tregs fully rescued obesity, insulin resistance, and fatty liver. Mechanistically, TKO Tregs exhibit reduced mitochondrial respiration and glycolysis, phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR signaling, and consequently impaired chemotactic properties. Collectively, our study identifies CD4 + T cell KLF10 as an essential regulator of obesity and insulin resistance by altering Treg metabolism and mobilization.

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  • KLF10 expression is significantly downregulated in Teffs and Tregs isolated from peripheral blood and spleen of high-fat diet-induced obese mice; conditional deletion of KLF10 in CD4+ T cells results in reduced Treg accumulation, leading to adipose tissue inflammation, insulin resistance, obesity, and MASLD; adoptive transfer of Tregs into these mice attenuates these features.

    “A recent study reported that KLF10 expression is significantly downregulated in Teffs and Tregs isolated from the peripheral blood and spleen of high-fat diet-induced obese mice (Wara et al. 2020). Moreover, the conditional deletion of KLF10 in CD4+ T cells results in reduced Treg accumulation, leading to adipose tissue inflammation, insulin resistance, obesity, and the development of MASLD (Wara”

    From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Wara et al. 2020

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Metadata

Authors
Wara, A. K., Wang, S., Wu, C., Fang, F., Haemmig, S., Weber, B. N., Aydogan, C. O., Tesmenitsky, Y., Aliakbarian, H., Hawse, J. R., Subramaniam, M., Zhao, L., Sage, P. T., Tavakkoli, A., Garza, A., Lynch, L., Banks, A. S., & Feinberg, M. W.
Affiliations
  • Brigham and Women's Hospital (US)
  • Mayo Clinic (US)
  • Istanbul University-Cerrahpaşa (TR)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
Feinberg, Mark W.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2020-12
Volume
33
Issue
13
Pages
108550
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2020.108550
PMC
PMC7816773
OpenAlex
W3116224770
Cited by
49
References
85
Citations by year
2026: 4 · 2025: 10 · 2024: 7 · 2023: 11 · 2022: 15 · 2021: 2
FWCI
5.02
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, other-oa)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • American Heart Association
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
KLF10, Krüppel-like factors, CD4+ T cells, regulatory T cells, obesity, insulin resistance, hepatic steatosis, TGF-beta3, mitochondrial respiration, glycolysis, PI3K/AKT/mTOR pathway, Treg metabolism, adipose tissue, liver
MeSH terms
Adipose Tissue, Animals, Cells, Cultured, Fatty Liver, Female, Gene Expression Regulation, Humans, Inflammation, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Mitochondria, Obesity, Signal Transduction, Mice, Knockout, Genetic Predisposition to Disease, T-Lymphocytes, Regulatory, Mice, Kruppel-Like Transcription Factors, Early Growth Response Transcription Factors, Transforming Growth Factor beta3, Phosphatidylinositol 3-Kinase

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