Reduced Oxidative Capacity in Macrophages Results in Systemic Insulin Resistance

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Apr 21

PMID 29674655

Citations 85

Authors

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

Minho Shong

Affiliations

Soon will be listed here.

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.

Citing Articles

Mitochondrial Regulator CRIF1 Plays a Critical Role in the Development and Homeostasis of Alveolar Macrophages via Maintaining Metabolic Fitness.

Lee E, Song S, Moon H, Shong M, Chung D Immune Netw. 2025; 25(1):e9.

PMID: 40078782 PMC: 11896662. DOI: 10.4110/in.2025.25.e9.

Relationship Between Brain Insulin Resistance, Carbohydrate Consumption, and Protein Carbonyls, and the Link Between Peripheral Insulin Resistance, Fat Consumption, and Malondialdehyde.

Salazar-Hernandez E, Bahena-Cuevas O, Mendoza-Bello J, Barragan-Bonilla M, Sanchez-Alavez M, Espinoza-Rojo M Biomedicines. 2025; 13(2).

PMID: 40002817 PMC: 11853321. DOI: 10.3390/biomedicines13020404.

The Downregulation of CRIF1 Exerts Antitumor Effects Partially via TP53-Induced Glycolysis and Apoptosis Regulator Induction in BT549 Breast Cancer Cells.

Piao S, Kim S, Vu G, Kim M, Lee E, Jeon B Cancers (Basel). 2024; 16(23).

PMID: 39682267 PMC: 11639960. DOI: 10.3390/cancers16234081.

GDF15/MIC-1: a stress-induced immunosuppressive factor which promotes the aging process.

Salminen A Biogerontology. 2024; 26(1):19.

PMID: 39643709 PMC: 11624233. DOI: 10.1007/s10522-024-10164-0.

ZBTB18 regulates cytokine expression and affects microglia/macrophage recruitment and commitment in glioblastoma.

Ferrarese R, Joseph K, Andrieux G, Haase I, Zanon F, Kling E Commun Biol. 2024; 7(1):1472.

PMID: 39516530 PMC: 11549471. DOI: 10.1038/s42003-024-07144-y.

References

Martinez F, Gordon S . The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6:13. PMC: 3944738. DOI: 10.12703/P6-13. View

Anthony R, Urban Jr J, Alem F, Hamed H, Rozo C, Boucher J . Memory T(H)2 cells induce alternatively activated macrophages to mediate protection against nematode parasites. Nat Med. 2006; 12(8):955-60. PMC: 1955764. DOI: 10.1038/nm1451. View

Johnen H, Kuffner T, Brown D, Wu B, Stocker R, Breit S . Increased expression of the TGF-b superfamily cytokine MIC-1/GDF15 protects ApoE(-/-) mice from the development of atherosclerosis. Cardiovasc Pathol. 2012; 21(6):499-505. DOI: 10.1016/j.carpath.2012.02.003. View

Rodriguez-Prados J, Traves P, Cuenca J, Rico D, Aragones J, Martin-Sanz P . Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol. 2010; 185(1):605-14. DOI: 10.4049/jimmunol.0901698. View

Bouhlel M, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S . PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab. 2007; 6(2):137-43. DOI: 10.1016/j.cmet.2007.06.010. View

Oh D, Morinaga H, Talukdar S, Bae E, Olefsky J . Increased macrophage migration into adipose tissue in obese mice. Diabetes. 2011; 61(2):346-54. PMC: 3266418. DOI: 10.2337/db11-0860. View

Huang S, Everts B, Ivanova Y, OSullivan D, Nascimento M, Smith A . Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol. 2014; 15(9):846-55. PMC: 4139419. DOI: 10.1038/ni.2956. View

Tsai V, Lin S, Brown D, Salis A, Breit S . Anorexia-cachexia and obesity treatment may be two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15. Int J Obes (Lond). 2015; 40(2):193-7. DOI: 10.1038/ijo.2015.242. View

Yang L, Chang C, Sun Z, Madsen D, Zhu H, Padkjaer S . GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med. 2017; 23(10):1158-1166. DOI: 10.1038/nm.4394. View

10.

Odegaard J, Chawla A . Alternative macrophage activation and metabolism. Annu Rev Pathol. 2010; 6:275-97. PMC: 3381938. DOI: 10.1146/annurev-pathol-011110-130138. View

11.

Villars F, Pietra C, Giuliano C, Lutz T, Riediger T . Oral Treatment with the Ghrelin Receptor Agonist HM01 Attenuates Cachexia in Mice Bearing Colon-26 (C26) Tumors. Int J Mol Sci. 2017; 18(5). PMC: 5454899. DOI: 10.3390/ijms18050986. View

12.

Borner T, Arnold M, Ruud J, Breit S, Langhans W, Lutz T . Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1/GDF15. J Cachexia Sarcopenia Muscle. 2016; 8(3):417-427. PMC: 5476861. DOI: 10.1002/jcsm.12169. View

13.

Montero R, Yubero D, Villarroya J, Henares D, Jou C, Rodriguez M . GDF-15 Is Elevated in Children with Mitochondrial Diseases and Is Induced by Mitochondrial Dysfunction. PLoS One. 2016; 11(2):e0148709. PMC: 4750949. DOI: 10.1371/journal.pone.0148709. View

14.

Dalmas E, Toubal A, Alzaid F, Blazek K, Eames H, Lebozec K . Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat Med. 2015; 21(6):610-8. DOI: 10.1038/nm.3829. View

15.

Kwon M, Koo B, Moon J, Kim Y, Park K, Kim N . Crif1 is a novel transcriptional coactivator of STAT3. EMBO J. 2008; 27(4):642-53. PMC: 2262042. DOI: 10.1038/sj.emboj.7601986. View

16.

Sica A, Bronte V . Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007; 117(5):1155-66. PMC: 1857267. DOI: 10.1172/JCI31422. View

17.

Olefsky J, Glass C . Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010; 72:219-46. DOI: 10.1146/annurev-physiol-021909-135846. View

18.

Artz A, Butz S, Vestweber D . GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-βRII heterodimer. Blood. 2016; 128(4):529-41. DOI: 10.1182/blood-2016-01-696617. View

19.

Odegaard J, Ricardo-Gonzalez R, Red Eagle A, Vats D, Morel C, Goforth M . Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 2008; 7(6):496-507. PMC: 2587370. DOI: 10.1016/j.cmet.2008.04.003. View

20.

Xie L, Fu Q, Ortega T, Zhou L, Rasmussen D, OKeefe J . Overexpression of IL-10 in C2D macrophages promotes a macrophage phenotypic switch in adipose tissue environments. PLoS One. 2014; 9(1):e86541. PMC: 3897709. DOI: 10.1371/journal.pone.0086541. View