Liver macrophages regulate systemic metabolism through non-inflammatory factors.

Nature Metabolism
Cecilia MorgantiniMyriam Aouadi

Abstract

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.

References

Sep 1, 1981·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·E R Weibel
Oct 3, 2003·Biochemical and Biophysical Research Communications·Sanjida AhmedKaoru Miyazaki
Feb 3, 2005·Nature Medicine·Melek C ArkanMichael Karin
Feb 26, 2005·Nucleic Acids Research·Erez Y LevanonEli Eisenberg
Jan 27, 2006·European Journal of Clinical Investigation·P PariniM Rudling
Apr 19, 2006·Journal of Hepatology·John Willy HaukelandPål Aukrust
Nov 14, 2006·Bioinformatics·S Falcon, R Gentleman
Nov 21, 2008·Reproductive Biology and Endocrinology : RB&E·Masahiko KutsukakeKazuhiro Tamura
Sep 22, 2009·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·Jeong-Hoon LeeHyo-Suk Lee
Oct 31, 2009·American Journal of Physiology. Gastrointestinal and Liver Physiology·Nicolas LanthierIsabelle A Leclercq
Jan 8, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Rinke StienstraMichael Müller
Jan 30, 2010·Bioinformatics·Aaron R Quinlan, Ira M Hall
Mar 4, 2010·Genome Biology·Mark D Robinson, Alicia Oshlack
Aug 4, 2010·Surgery for Obesity and Related Diseases : Official Journal of the American Society for Bariatric Surgery·Olga T HardyMichael P Czech
Nov 3, 2010·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Herbert Tilg, Alexander R Moschen
Mar 23, 2011·The Biochemical Journal·Gregory J TeszMichael P Czech
Aug 30, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Nicolas LanthierIsabelle A Leclercq
May 16, 2012·Advances in Nutrition·Mary Courtney MooreAlan D Cherrington
Jul 4, 2012·FEBS Letters·Christina Godfried SieMichael Kuchka
Nov 30, 2012·Nucleic Acids Research·Tanya BarrettAlexandra Soboleva
Dec 20, 2012·Science Signaling·Valentina EvdokimovaArun Seth
Jun 5, 2013·Molecular and Cellular Endocrinology·Ping JiaoHaiyan Xu
Mar 19, 2014·Methods : a Companion to Methods in Enzymology·Jason M TennessenCarl S Thummel
May 24, 2014·Nature Reviews. Drug Discovery·Marc Y Donath
Oct 15, 2014·Proceedings of the National Academy of Sciences of the United States of America·Steve HorvathJochen Hampe
Oct 28, 2014·Expert Opinion on Investigational Drugs·Nathalie EsserAndré J Scheen
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Jan 22, 2015·Nucleic Acids Research·Matthew E RitchieGordon K Smyth

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Citations

Apr 10, 2019·Nature Reviews. Immunology·Kirsty Minton
Apr 18, 2019·Nature Reviews. Endocrinology·Alan Morris
Feb 28, 2020·Science Translational Medicine·Valerio AzzimatoMyriam Aouadi
Mar 7, 2020·Frontiers in Endocrinology·Lucie OrliaguetFawaz Alzaid
Oct 31, 2020·The Journal of Clinical Endocrinology and Metabolism·Takara L StanleySteven K Grinspoon
Dec 24, 2019·Cell Metabolism·Paul PetrusMikael Rydén
Nov 13, 2020·Frontiers in Immunology·Torsten P M ScheithauerHilde Herrema
Mar 5, 2021·Frontiers in Cell and Developmental Biology·Adam BajgarTomáš Doležal
Apr 20, 2021·Basic & Clinical Pharmacology & Toxicology·Magnus Ingelman-Sundberg, Volker M Lauschke
Jun 25, 2021·Advanced Science·Joanne X ShenVolker M Lauschke
Jun 29, 2021·Frontiers in Immunology·Christian ZwickerCharlotte L Scott
Sep 2, 2021·Immunity·Camille BlériotFlorent Ginhoux
Sep 17, 2020·Immunity·Ehud Zigmond, Chen Varol
Aug 27, 2021·Blood Advances·Leonardo Luís ArticoJosé Andrés Yunes
Aug 24, 2021·Gastroenterology·Valerio AzzimatoMyriam Aouadi

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Datasets Mentioned

BETA
GSE48452

Methods Mentioned

BETA
RNA-seq
flow cytometry
FACS
ELISA
transmission electron microscopy
electron
immunoprecipitations
immunoprecipitation
coimmunoprecipitation
gastric bypass

Software Mentioned

TopHat
limma
GraphPad Prism
bcl2fastq
DESeq2
BWA
GO stats package
Ensembl
FlowJo
BEDTools

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