GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
GRK2 levels in myeloid cells modulate adipose‑liver crosstalk in high fat diet‑induced obesity Rocío Vila‑Bedmar1 · Marta Cruces‑Sande2,3,4 · Alba C. Arcones2,3,4 · Hanneke L. D. M. Willemen5 · Patricia Prieto4,6 · Isabel Moreno‑Indias7,8 · Daniel Díaz‑Rodríguez2 · Sara Francisco2 · Rafael I. Jaén6 · Carolina Gutiérrez‑Repiso7,8 · Cobi J. Heijnen9 · Lisardo Boscá4,6 · Manuel Fresno2,3 · Annemieke Kavelaars9 · Federico Mayor Jr2,3,4 · Cristina Murga2,3,4 Received: 26 July 2019 / Revised: 18 December 2019 / Accepted: 23 December 2019 © Springer Nature Switzerland AG 2020
Abstract Macrophages are key effector cells in obesity-associated inflammation. G protein-coupled receptor kinase 2 (GRK2) is highly expressed in different immune cell types. Using LysM-GRK2+/− mice, we uncover that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) through modulation of the macrophage pro-inflammatory profile. Low levels of myeloid GRK2 confer protection against hepatic insulin resistance, steatosis and inflammation. In adipose tissue, pro-inflammatory cytokines are reduced and insulin signaling is preserved. Macrophages from LysM-GRK2+/− mice secrete less pro-inflammatory cytokines when stimulated with lipopolysaccharide (LPS) and their conditioned media has a reduced pathological influence in cultured adipocytes or naïve bone marrow-derived macrophages. Our data indicate that reducing GRK2 levels in myeloid cells, by attenuating pro-inflammatory features of macrophages, has a relevant impact in adipose-liver crosstalk, thus preventing high fat diet-induced metabolic alterations. Keywords Obesity · Macrophages · GRK2 · Liver · Adipose tissue · Glucose homeostasis Abbreviations BMDM Bone marrow-derived macrophages CM Conditioned media COX-2 Cyclooxygenase-2 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-019-03442-5) contains supplementary material, which is available to authorized users. * Federico Mayor Jr [email protected] * Cristina Murga [email protected] 1
Departamento de ciencias básicas de la salud, área de Bioquímica y Biología Molecular, Universidad Rey Juan Carlos (URJC), Madrid, Spain
2
Departamento de Biología Molecular and Centro de Biología Molecular “Severo Ochoa”, Universidad Autónoma de Madrid (CSIC/UAM), C/Nicolás Cabrera 1, 28049 Madrid, Spain
3
Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
4
CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
FA Fatty acids GRK2 G protein-coupled receptor kinase 2 GTT Glucose tolerance test HFD High fat diet HO-1 Heme oxygenase-1 iNOS Inducible nitric oxide synthase IR Insulin resistance 5
Laboratory of Translational Immunology (LTI), University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
6
Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM),
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