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

Akm Khyrul Wara, Shijia Wang, Chun Wu, Fang Fang, Stefan Haemmig, Brittany N. Weber, Ceren O. Aydogan, Yevgenia Tesmenitsky, Hassan Aliakbarian, John R. Hawse, Malayannan Subramaniam, Lei Zhao, Peter T. Sage, Ali Tavakkoli, Amanda Garza, Lydia Lynch, Alexander S. Banks, Mark W. Feinberg

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number108550
JournalCell reports
Volume33
Issue number13
DOIs
StatePublished - Dec 29 2020

Keywords

  • CD4 T cell
  • KLF10
  • PI3K-Akt-mTOR pathway
  • Treg
  • glycolysis
  • metabolic disorders
  • mitochondria
  • obesity
  • oxidative phosphorylation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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