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      Reduced oxidative capacity in macrophages results in systemic insulin resistance

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          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.

          Abstract

          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.

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          Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance.

          Obesity and insulin resistance, the cardinal features of metabolic syndrome, are closely associated with a state of low-grade inflammation. In adipose tissue chronic overnutrition leads to macrophage infiltration, resulting in local inflammation that potentiates insulin resistance. For instance, transgenic expression of Mcp1 (also known as chemokine ligand 2, Ccl2) in adipose tissue increases macrophage infiltration, inflammation and insulin resistance. Conversely, disruption of Mcp1 or its receptor Ccr2 impairs migration of macrophages into adipose tissue, thereby lowering adipose tissue inflammation and improving insulin sensitivity. These findings together suggest a correlation between macrophage content in adipose tissue and insulin resistance. However, resident macrophages in tissues display tremendous heterogeneity in their activities and functions, primarily reflecting their local metabolic and immune microenvironment. While Mcp1 directs recruitment of pro-inflammatory classically activated macrophages to sites of tissue damage, resident macrophages, such as those present in the adipose tissue of lean mice, display the alternatively activated phenotype. Despite their higher capacity to repair tissue, the precise role of alternatively activated macrophages in obesity-induced insulin resistance remains unknown. Using mice with macrophage-specific deletion of the peroxisome proliferator activated receptor-gamma (PPARgamma), we show here that PPARgamma is required for maturation of alternatively activated macrophages. Disruption of PPARgamma in myeloid cells impairs alternative macrophage activation, and predisposes these animals to development of diet-induced obesity, insulin resistance, and glucose intolerance. Furthermore, gene expression profiling revealed that downregulation of oxidative phosphorylation gene expression in skeletal muscle and liver leads to decreased insulin sensitivity in these tissues. Together, our findings suggest that resident alternatively activated macrophages have a beneficial role in regulating nutrient homeostasis and suggest that macrophage polarization towards the alternative state might be a useful strategy for treating type 2 diabetes.
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            Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

            The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue homeostasis, metabolism, and endocrine signaling. Today the M2 macrophages are identified based on the expression pattern of a set of M2 markers. These markers are transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. This review discusses whether these M2 markers can be reliably used to identify M2 macrophages and define their functional subdivisions. Also, it provides an update on the novel signals of the tissue environment and the neuroendocrine system which shape the M2 activation. The possible evolutionary roots of the M2 macrophage functions are also discussed.
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              Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation.

              Complex interplay between T helper (Th) cells and macrophages contributes to the formation and progression of atherosclerotic plaques. While Th1 cytokines promote inflammatory activation of lesion macrophages, Th2 cytokines attenuate macrophage-mediated inflammation and enhance their repair functions. In spite of its biologic importance, the biochemical and molecular basis of how Th2 cytokines promote maturation of anti-inflammatory macrophages is not understood. We show here that in response to interleukin-4 (IL-4), signal transducer and activator of transcription 6 (STAT6) and PPARgamma-coactivator-1beta (PGC-1beta) induce macrophage programs for fatty acid oxidation and mitochondrial biogenesis. Transgenic expression of PGC-1beta primes macrophages for alternative activation and strongly inhibits proinflammatory cytokine production, whereas inhibition of oxidative metabolism or RNAi-mediated knockdown of PGC-1beta attenuates this immune response. These data elucidate a molecular pathway that directly links mitochondrial oxidative metabolism to the anti-inflammatory program of macrophage activation, suggesting a potential role for metabolic therapies in treating atherogenic inflammation.
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                Author and article information

                Contributors
                +82-42-280-7161 , minhos@cnu.ac.kr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                19 April 2018
                19 April 2018
                2018
                : 9
                : 1551
                Affiliations
                [1 ]ISNI 0000 0001 0722 6377, GRID grid.254230.2, Research Center for Endocrine and Metabolic Diseases, Department of Medical Science, School of Medicine, , Chungnam National University, ; Daejeon, 35015 Korea
                [2 ]ISNI 0000000121839049, GRID grid.5333.6, Laboratory for Integrative and Systems Physiology, Institute of Bioengineering, , École Polytechnique Fédérale de Lausanne, ; 1015 Lausanne, Switzerland
                [3 ]ISNI 0000 0001 0719 8572, GRID grid.262229.f, Laboratory of Molecular and Integrative Biology, Department of Korean Medical Science, School of Korean Medicine, , Pusan National University, ; Yangsan, 50612 Korea
                [4 ]ISNI 0000 0004 0647 2279, GRID grid.411665.1, Department of Internal Medicine, , Chungnam National University Hospital, ; Daejeon, 35015 Korea
                [5 ]ISNI 0000 0001 0722 6377, GRID grid.254230.2, Department of Physiology, Department of Medical Science, School of Medicine, , Chungnam National University, ; Daejeon, 35015 Korea
                [6 ]ISNI 0000 0004 0636 3099, GRID grid.249967.7, Laboratory Animal Resource Center, , Korea Research Institute of Bioscience and Biotechnology, ; Daejeon, 34141 Korea
                [7 ]ISNI 0000 0004 0386 9246, GRID grid.267301.1, Department of Genetics, Genomics and Informatics, , University of Tennessee Health Science Center, ; Memphis, TN 38163 USA
                [8 ]ISNI 0000 0001 2292 0500, GRID grid.37172.30, Graduate School of Medical Science and Engineering, , Korea Advanced Institute of Science and Technology, ; Daejeon, 34051 Korea
                Author information
                http://orcid.org/0000-0002-3977-1510
                Article
                3998
                10.1038/s41467-018-03998-z
                5908799
                29674655
                aa5ccdb8-cedb-4e51-bae4-a8877f77502b
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 16 September 2017
                : 27 March 2018
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