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Nat Commun. 2018 Apr 19;9(1):1551. doi: 10.1038/s41467-018-03998-z.

Reduced oxidative capacity in macrophages results in systemic insulin resistance.

Author information

1
Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea.
2
Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland.
3
Laboratory of Molecular and Integrative Biology, Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, 50612, Korea.
4
Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, Korea.
5
Department of Physiology, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea.
6
Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea.
7
Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
8
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34051, Korea.
9
Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. minhos@cnu.ac.kr.
10
Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, Korea. minhos@cnu.ac.kr.

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.

PMID:
29674655
PMCID:
PMC5908799
DOI:
10.1038/s41467-018-03998-z
[Indexed for MEDLINE]
Free PMC Article

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