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GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity

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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.

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Abbreviations

BMDM:

Bone marrow-derived macrophages

CM:

Conditioned media

COX-2:

Cyclooxygenase-2

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

ITT:

Insulin tolerance test

LPS:

Lipopolysaccharide

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

PTT:

Pyruvate tolerance test

TEPMs:

Thioglycollate -elicited peritoneal macrophages

TG:

Triglycerides

TLR:

Toll-like receptor

WAT:

White adipose tissue

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Acknowledgements

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.

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Authors and Affiliations

  1. Departamento de ciencias básicas de la salud, área de Bioquímica y Biología Molecular, Universidad Rey Juan Carlos (URJC), Madrid, Spain

    Rocío Vila-Bedmar

  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

    Marta Cruces-Sande, Alba C. Arcones, Daniel Díaz-Rodríguez, Sara Francisco, Manuel Fresno, Federico Mayor Jr & Cristina Murga

  3. Instituto de Investigación Sanitaria La Princesa, Madrid, Spain

    Marta Cruces-Sande, Alba C. Arcones, Manuel Fresno, Federico Mayor Jr & Cristina Murga

  4. CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    Marta Cruces-Sande, Alba C. Arcones, Patricia Prieto, Lisardo Boscá, Federico Mayor Jr & Cristina Murga

  5. Laboratory of Translational Immunology (LTI), University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Hanneke L. D. M. Willemen

  6. Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain

    Patricia Prieto, Rafael I. Jaén & Lisardo Boscá

  7. CIBER de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    Isabel Moreno-Indias & Carolina Gutiérrez-Repiso

  8. Instituto de Investigación Biomédica de Málaga (IBIMA), Unidad de Endocrinología y Nutrición, Hospital Universitario Virgen de Victoria de Malaga, Universidad de Málaga, Málaga, Spain

    Isabel Moreno-Indias & Carolina Gutiérrez-Repiso

  9. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Cobi J. Heijnen & Annemieke Kavelaars

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  1. Rocío Vila-Bedmar
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Vila-Bedmar, R., Cruces-Sande, M., Arcones, A.C. et al. GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity. Cell. Mol. Life Sci. 77, 4957–4976 (2020). https://doi.org/10.1007/s00018-019-03442-5

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