Myeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation

David R. Sweet, Neelakantan T. Vasudevan, Liyan Fan, Chloe E. Booth, Komal S. Keerthy, Xudong Liao, Vinesh Vinayachandran, Yoichi Takami, Derin Tugal, Nikunj Sharma, E. Ricky Chan, Lilei Zhang, Yulan Qing, Stanton L. Gerson, Chen Fu, Anthony Wynshaw-Boris, Panjamaporn Sangwung, Lalitha Nayak, Paul Holvoet, Keiichiro Matoba, Yuan Lu, Guangjin Zhou and Mukesh K. Jain ()
Additional contact information
David R. Sweet: University Hospitals Cleveland Medical Center
Neelakantan T. Vasudevan: University Hospitals Cleveland Medical Center
Liyan Fan: University Hospitals Cleveland Medical Center
Chloe E. Booth: University Hospitals Cleveland Medical Center
Komal S. Keerthy: University Hospitals Cleveland Medical Center
Xudong Liao: University Hospitals Cleveland Medical Center
Vinesh Vinayachandran: University Hospitals Cleveland Medical Center
Yoichi Takami: Osaka University Graduate School of Medicine
Derin Tugal: Beth Israel Deaconess Medical Center and Harvard Medical School
Nikunj Sharma: Food and Drug Administration
E. Ricky Chan: Case Western Reserve University
Lilei Zhang: Baylor College of Medicine
Yulan Qing: Case Western Reserve University
Stanton L. Gerson: Case Western Reserve University
Chen Fu: Case Western Reserve University, and University Hospitals Cleveland Medical Center
Anthony Wynshaw-Boris: Case Western Reserve University, and University Hospitals Cleveland Medical Center
Panjamaporn Sangwung: University Hospitals Cleveland Medical Center
Lalitha Nayak: University Hospitals Cleveland Medical Center
Paul Holvoet: KU Leuven
Keiichiro Matoba: University Hospitals Cleveland Medical Center
Yuan Lu: University Hospitals Cleveland Medical Center
Guangjin Zhou: University Hospitals Cleveland Medical Center
Mukesh K. Jain: University Hospitals Cleveland Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract Substantial evidence implicates crosstalk between metabolic tissues and the immune system in the inception and progression of obesity. However, molecular regulators that orchestrate metaflammation both centrally and peripherally remains incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. In mice and humans, consumption of a fatty diet downregulates myeloid KLF2 levels. Under basal conditions, myeloid-specific KLF2 knockout mice (K2KO) exhibit increased feeding and weight gain. High-fat diet (HFD) feeding further exacerbates the K2KO metabolic disease phenotype. Mechanistically, loss of myeloid KLF2 increases metaflammation in peripheral and central tissues. A combination of pair-feeding, bone marrow-transplant, and microglial ablation implicate central and peripheral contributions to K2KO-induced metabolic dysfunction observed. Finally, overexpression of myeloid KLF2 protects mice from HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a nodal regulator of central and peripheral metabolic inflammation in homeostasis and disease.

Date: 2020
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DOI: 10.1038/s41467-020-19760-3

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