Liver macrophages (LMs) have been proposed to contribute to metabolic disease through secretion of inflammatory cytokines. However, anti-inflammatory drugs lead to only modest improvements in systemic metabolism. Here we show that LMs do not undergo a proinflammatory phenotypic switch in obesity-induced insulin resistance in flies, mice and humans. Instead, we find that LMs produce non-inflammatory factors, such as insulin-like growth factor-binding protein 7 (IGFBP7), that directly regulate liver metabolism. IGFBP7 binds to the insulin receptor and induces lipogenesis and gluconeogenesis via activation of extracellular-signal-regulated kinase (ERK) signalling. We further show that IGFBP7 is subject to RNA editing at a higher frequency in insulin-resistant than in insulin-sensitive obese patients (90% versus 30%, respectively), resulting in an IGFBP7 isoform with potentially higher capacity to bind to the insulin receptor. Our study demonstrates that LMs can contribute to insulin resistance independently of their inflammatory status and indicates that non-inflammatory factors produced by macrophages might represent new drug targets for the treatment of metabolic diseases.

Bioscience Cardiovascular Renal and Metabolism IMED Biotech Unit AstraZeneca Gothenburg Sweden

Center for Infectious Medicine Department of Medicine Huddinge Karolinska Institutet Karolinska University Hospital Stockholm Sweden

Department of Laboratory Medicine Clinical Research Center Karolinska Institutet Huddinge Sweden

Department of Microbiology Tumor and Cell Biology Science for Life Laboratory Karolinska Institutet Stockholm Sweden

Department of Molecular Endocrinology KMEB University of Southern Denmark Odense University Hospital and Danish Diabetes Academy Odense Denmark

Department of Molecular Mechanisms of Disease University of Zurich Zurich Switzerland

Division of Surgery Department of Clinical Sciences Danderyd Hospital Karolinska Institutet Stockholm Sweden

Division of Transplantation Surgery CLINTEC Karolinska Institutet Huddinge Sweden

Faculty of Science University of South Bohemia and Institute of Entomology Biology Centre Czech Academy of Sciences Ceske Budejovice Czech Republic

Integrated Cardio Metabolic Center Department of Medicine Karolinska Institutet Huddinge Sweden

Laboratory of Evolutionary Protistology Institute of Parasitology Biology Centre Czech Academy of Sciences Ceske Budejovice Czech Republic

Metabolism Unit C2 94 Department of Medicine and Center for Innovative Medicine Department of Biosciences and Nutrition Karolinska Institutet Huddinge Stockholm Sweden

Section of Pharmacogenetics Department of Physiology and Pharmacology Karolinska Institutet Solna Sweden

Translational Sciences Cardiovascular Renal and Metabolic Diseases IMED Biotech Unit AstraZeneca Gothenburg Sweden

Unit of Endocrinology Department of Medicine Karolinska Institutet Huddinge Sweden

Université Nice Côte d'Azur INSERM U1065 C3M Team Cellular and Molecular Physiopathology of Obesity Nice France

Wallenberg Centre for Molecular and Translational Medicine Lundberg Laboratory for Diabetes Research University of Gothenburg Gothenburg Sweden

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$a Liver macrophages regulate systemic metabolism through non-inflammatory factors / $c C. Morgantini, J. Jager, X. Li, L. Levi, V. Azzimato, A. Sulen, E. Barreby, C. Xu, M. Tencerova, E. Näslund, C. Kumar, F. Verdeguer, S. Straniero, K. Hultenby, NK. Björkström, E. Ellis, M. Rydén, C. Kutter, T. Hurrell, VM. Lauschke, J. Boucher, A. Tomčala, G. Krejčová, A. Bajgar, M. Aouadi

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$a Liver macrophages (LMs) have been proposed to contribute to metabolic disease through secretion of inflammatory cytokines. However, anti-inflammatory drugs lead to only modest improvements in systemic metabolism. Here we show that LMs do not undergo a proinflammatory phenotypic switch in obesity-induced insulin resistance in flies, mice and humans. Instead, we find that LMs produce non-inflammatory factors, such as insulin-like growth factor-binding protein 7 (IGFBP7), that directly regulate liver metabolism. IGFBP7 binds to the insulin receptor and induces lipogenesis and gluconeogenesis via activation of extracellular-signal-regulated kinase (ERK) signalling. We further show that IGFBP7 is subject to RNA editing at a higher frequency in insulin-resistant than in insulin-sensitive obese patients (90% versus 30%, respectively), resulting in an IGFBP7 isoform with potentially higher capacity to bind to the insulin receptor. Our study demonstrates that LMs can contribute to insulin resistance independently of their inflammatory status and indicates that non-inflammatory factors produced by macrophages might represent new drug targets for the treatment of metabolic diseases.

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