TY - JOUR
T1 - GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity
AU - Vila-Bedmar, Rocío
AU - Cruces-Sande, Marta
AU - Arcones, Alba C
AU - Willemen, Hanneke L D M
AU - Prieto, Patricia
AU - Moreno-Indias, Isabel
AU - Díaz-Rodríguez, Daniel
AU - Francisco, Sara
AU - Jaén, Rafael I
AU - Gutiérrez-Repiso, Carolina
AU - Heijnen, Cobi J
AU - Boscá, Lisardo
AU - Fresno, Manuel
AU - Kavelaars, Annemieke
AU - Mayor, Federico
AU - Murga, Cristina
N1 - Funding Information:
We acknowledge support by Ministerio de Economía y Competitividad (MINECO/FEDER), Spain (grant SAF2017-84125-R to FM and CM and SAF2017-82436R to LB); CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, Spain (grant CB16/11/00278 to F.M., CB16/11/00222 to L.B., and, PI15/01114 to Francisco Tinaones (Universidad De Málaga, Spain), co-funded with European FEDER contribution); European Foundation for the Study of Diabetes (EFSD) Novo Nordisk Partnership for Diabetes Research in Europe Grant (to F.M.); and Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to FM and MF.. I.M.-I. was supported by the “MS type I” program (CP16/00163). The authors thank the Metagenomic Platform of the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición, CIBERobn, Instituto de Salud Carlos III (ISCIII), Spain. We appreciate the help of the CBMSO Facilities, in particular Flow Cytometry, Genomics and Animal Care. We acknowledge Paula Ramos for technical support. We also acknowledge the institutional support to the CBMSO from Fundación Ramón Areces.
Funding Information:
We acknowledge support by Ministerio de Econom?a y Competitividad (MINECO/FEDER), Spain (grant SAF2017-84125-R to FM and CM and SAF2017-82436R to LB); CIBER de Enfermedades Cardiovasculares (CIBERCV). Instituto de Salud Carlos III, Spain (grant CB16/11/00278 to F.M., CB16/11/00222 to L.B., and, PI15/01114 to Francisco Tinaones (Universidad De M?laga, Spain), co-funded with European FEDER contribution); European Foundation for the Study of Diabetes (EFSD) Novo Nordisk Partnership for Diabetes Research in Europe Grant (to F.M.); and Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE to FM and MF. I.M.-I. was supported by the ?MS type I? program (CP16/00163). The authors thank the Metagenomic Platform of the Centro de Investigaci?n Biom?dica en Red de Fisiopatolog?a de la Obesidad y la Nutrici?n, CIBERobn, Instituto de Salud Carlos III (ISCIII), Spain. We appreciate the help of the CBMSO Facilities, in particular Flow Cytometry, Genomics and Animal Care. We acknowledge Paula Ramos for technical support. We also acknowledge the institutional support to the CBMSO from Fundaci?n Ram?n Areces.
Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
KW - Adipose tissue
KW - GRK2
KW - Glucose homeostasis
KW - Liver
KW - Macrophages
KW - Obesity
KW - Cytoprotection/drug effects
KW - Myeloid Cells/drug effects
KW - Fatty Liver/complications
KW - G-Protein-Coupled Receptor Kinase 2/metabolism
KW - Glucose Intolerance/metabolism
KW - Adipose Tissue/metabolism
KW - Diet, High-Fat
KW - Liver/metabolism
KW - Insulin/metabolism
KW - Gastrointestinal Microbiome/drug effects
KW - Glucose/metabolism
KW - Adipose Tissue, White/pathology
KW - Inflammation/pathology
KW - Mice, Inbred C57BL
KW - Insulin Resistance
KW - Macrophages, Peritoneal/drug effects
KW - Signal Transduction/drug effects
KW - Adipocytes/drug effects
KW - Animals
KW - Culture Media, Conditioned/pharmacology
KW - Models, Biological
KW - Obesity/complications
KW - Weight Gain/drug effects
KW - Hypertrophy
UR - https://www.scopus.com/pages/publications/85077681301
U2 - 10.1007/s00018-019-03442-5
DO - 10.1007/s00018-019-03442-5
M3 - Article
C2 - 31927610
SN - 1420-682X
VL - 77
SP - 4957
EP - 4976
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 23
ER -