PMID- 29674655 OWN - NLM STAT- MEDLINE DCOM- 20190102 LR - 20190419 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 9 IP - 1 DP - 2018 Apr 19 TI - Reduced oxidative capacity in macrophages results in systemic insulin resistance. PG - 1551 LID - 10.1038/s41467-018-03998-z [doi] LID - 1551 AB - 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. FAU - Jung, Saet-Byel AU - Jung SB AD - Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. FAU - Choi, Min Jeong AU - Choi MJ AD - Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. FAU - Ryu, Dongryeol AU - Ryu D AD - Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, 1015, Lausanne, Switzerland. AD - Laboratory of Molecular and Integrative Biology, Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, 50612, Korea. FAU - Yi, Hyon-Seung AU - Yi HS AD - Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, Korea. FAU - Lee, Seong Eun AU - Lee SE AD - Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. FAU - Chang, Joon Young AU - Chang JY AD - Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. FAU - Chung, Hyo Kyun AU - Chung HK AD - Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. FAU - Kim, Yong Kyung AU - Kim YK AD - Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. FAU - Kang, Seul Gi AU - Kang SG AD - Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. FAU - Lee, Ju Hee AU - Lee JH AD - Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, Korea. FAU - Kim, Koon Soon AU - Kim KS AD - Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. AD - Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, Korea. FAU - Kim, Hyun Jin AU - Kim HJ AD - Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, Korea. FAU - Kim, Cuk-Seong AU - Kim CS AD - Department of Physiology, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. FAU - Lee, Chul-Ho AU - Lee CH AD - Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Korea. FAU - Williams, Robert W AU - Williams RW AD - Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, 38163, USA. FAU - Kim, Hail AU - Kim H AD - Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34051, Korea. FAU - Lee, Heung Kyu AU - Lee HK AUID- ORCID: 0000-0002-3977-1510 AD - Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34051, Korea. FAU - Auwerx, Johan AU - Auwerx J AD - Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Federale de Lausanne, 1015, Lausanne, Switzerland. FAU - Shong, Minho AU - Shong M AD - Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, Chungnam National University, Daejeon, 35015, Korea. minhos@cnu.ac.kr. AD - Department of Internal Medicine, Chungnam National University Hospital, Daejeon, 35015, Korea. minhos@cnu.ac.kr. LA - eng GR - R01 AG043930/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180419 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Cell Cycle Proteins) RN - 0 (Crif1 protein, mouse) RN - 0 (Gdf15 protein, mouse) RN - 0 (Growth Differentiation Factor 15) RN - 207137-56-2 (Interleukin-4) SB - IM MH - Adipose Tissue MH - Animals MH - Cell Cycle Proteins/genetics/metabolism MH - Growth Differentiation Factor 15/genetics/metabolism MH - *Insulin Resistance MH - Interleukin-4/genetics/metabolism MH - Macrophages/*metabolism MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Mitochondria/metabolism MH - Obesity/genetics/*metabolism MH - *Oxidative Phosphorylation MH - Oxidative Stress PMC - PMC5908799 COIS- The authors declare no competing interests. EDAT- 2018/04/21 06:00 MHDA- 2019/01/03 06:00 PMCR- 2018/04/19 CRDT- 2018/04/21 06:00 PHST- 2017/09/16 00:00 [received] PHST- 2018/03/27 00:00 [accepted] PHST- 2018/04/21 06:00 [entrez] PHST- 2018/04/21 06:00 [pubmed] PHST- 2019/01/03 06:00 [medline] PHST- 2018/04/19 00:00 [pmc-release] AID - 10.1038/s41467-018-03998-z [pii] AID - 3998 [pii] AID - 10.1038/s41467-018-03998-z [doi] PST - epublish SO - Nat Commun. 2018 Apr 19;9(1):1551. doi: 10.1038/s41467-018-03998-z.