Reduced oxidative capacity in macrophages results in systemic insulin resistance

Saet-Byel Jung, Min Jeong Choi, Dongryeol Ryu, Hyon-Seung Yi, Seong Eun Lee, Joon Young Chang, Hyo Kyun Chung, Yong Kyung Kim, Seul Gi Kang, Ju Hee Lee, Koon Soon Kim, Hyun Jin Kim, Cuk-Seong Kim, Chul-Ho Lee, Robert W. Williams, Hail Kim, Heung Kyu Lee, Johan Auwerx and Minho Shong ()
Additional contact information
Saet-Byel Jung: Chungnam National University
Min Jeong Choi: Chungnam National University
Dongryeol Ryu: École Polytechnique Fédérale de Lausanne
Hyon-Seung Yi: Chungnam National University Hospital
Seong Eun Lee: Chungnam National University
Joon Young Chang: Chungnam National University
Hyo Kyun Chung: Chungnam National University
Yong Kyung Kim: Chungnam National University
Seul Gi Kang: Chungnam National University
Ju Hee Lee: Chungnam National University Hospital
Koon Soon Kim: Chungnam National University
Hyun Jin Kim: Chungnam National University Hospital
Cuk-Seong Kim: Chungnam National University
Chul-Ho Lee: Korea Research Institute of Bioscience and Biotechnology
Robert W. Williams: University of Tennessee Health Science Center
Hail Kim: Korea Advanced Institute of Science and Technology
Heung Kyu Lee: Korea Advanced Institute of Science and Technology
Johan Auwerx: École Polytechnique Fédérale de Lausanne
Minho Shong: Chungnam National University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Oxidative functions of adipose tissue macrophages control the polarization of M1-like and M2-like phenotypes, but whether reduced macrophage oxidative function causes systemic insulin resistance in vivo is not clear. Here, we show that mice with reduced mitochondrial oxidative phosphorylation (OxPhos) due to myeloid-specific deletion of CR6-interacting factor 1 (Crif1), an essential mitoribosomal factor involved in biogenesis of OxPhos subunits, have M1-like polarization of macrophages and systemic insulin resistance with adipose inflammation. Macrophage GDF15 expression is reduced in mice with impaired oxidative function, but induced upon stimulation with rosiglitazone and IL-4. GDF15 upregulates the oxidative function of macrophages, leading to M2-like polarization, and reverses insulin resistance in ob/ob mice and HFD-fed mice with myeloid-specific deletion of Crif1. Thus, reduced macrophage oxidative function controls systemic insulin resistance and adipose inflammation, which can be reversed with GDF15 and leads to improved oxidative function of macrophages.

Date: 2018
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DOI: 10.1038/s41467-018-03998-z

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