Reduced oxidative capacity in macrophages results in systemic insulin resistance

• Published in: Nature communications Vol. 9; no. 1; pp. 1551 - 15
• Main Authors: Jung, Saet-Byel, Choi, Min Jeong, Ryu, Dongryeol, Yi, Hyon-Seung, Lee, Seong Eun, Chang, Joon Young, Chung, Hyo Kyun, Kim, Yong Kyung, Kang, Seul Gi, Lee, Ju Hee, Kim, Koon Soon, Kim, Hyun Jin, Kim, Cuk-Seong, Lee, Chul-Ho, Williams, Robert W., Kim, Hail, Lee, Heung Kyu, Auwerx, Johan, Shong, Minho
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.04.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 13/51; 38/109; 38/22; 38/44; 38/77; 38/90; 631/250/256/2515; 692/163/2743/137/773; 692/163/2743/2037; 692/163/2743/393; Adipose Tissue; Animal models; Animals; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Growth Differentiation Factor 15 - genetics; Growth Differentiation Factor 15 - metabolism; Humanities and Social Sciences; Insulin; Insulin Resistance; Interleukin 4; Interleukin-4 - genetics; Interleukin-4 - metabolism; Macrophages; Macrophages - metabolism; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; multidisciplinary; Obesity - genetics; Obesity - metabolism; Oxidation resistance; Oxidative Phosphorylation; Oxidative Stress; Phosphorylation; Polarization; Rosiglitazone; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03998-z

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. M1-like polarization of macrophages is thought to control adipose inflammation and associated insulin resistance and metabolic syndrome. Here the authors show that macrophage-specific deletion of the OxPhos-related gene Crif1 results in an M1-like phenotype in mice, and that the effects can be reversed by recombinant GDF15.