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


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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8



Bone marrow-derived macrophages


Conditioned media




Fatty acids


G protein-coupled receptor kinase 2


Glucose tolerance test


High fat diet


Heme oxygenase-1


Inducible nitric oxide synthase


Insulin resistance


Insulin tolerance test




Non-alcoholic fatty liver disease


Non-alcoholic steatohepatitis


Pyruvate tolerance test


Thioglycollate -elicited peritoneal macrophages




Toll-like receptor


White adipose tissue


  1. 1.

    Younossi Z, Tacke F, Arrese M, Sharma BC, Mostafa I, Bugianesi E, Wong VW, Yilmaz Y, George J, Fan J, Vos MB (2018) Global perspectives on non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Hepatology.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156(1–2):20–44.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Investig 117(1):175–184.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Lumeng CN, DelProposto JB, Westcott DJ, Saltiel AR (2008) Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 57(12):3239–3246.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Olefsky JM, Glass CK (2010) Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 72:219–246.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Odegaard JI, Chawla A (2008) Mechanisms of macrophage activation in obesity-induced insulin resistance. Nat Clin Pract Endocrinol Metab 4(11):619–626.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Cusi K (2012) Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142(4):711–725.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, Peduto T, Chisholm DJ, George J (2008) Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48(2):449–457.

    Article  PubMed  Google Scholar 

  10. 10.

    Kazankov K, Jorgensen SMD, Thomsen KL, Moller HJ, Vilstrup H, George J, Schuppan D, Gronbaek H (2019) The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 16(3):145–159.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nat Rev Immunol 11(2):85–97.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig 112(12):1796–1808.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Cani PD, Everard A, Duparc T (2013) Gut microbiota, enteroendocrine functions and metabolism. Curr Opin Pharmacol 13(6):935–940.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Shen J, Obin MS, Zhao L (2013) The gut microbiota, obesity and insulin resistance. Mol Aspects Med 34(1):39–58.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Musso G, Gambino R, Cassader M (2011) Interactions between gut microbiota and host metabolism predisposing to obesity and diabetes. Annu Rev Med 62:361–380.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56(7):1761–1772.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Investig 116(11):3015–3025.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biolog Chem 282(48):35279–35292.

    CAS  Article  Google Scholar 

  20. 20.

    Biswas SK, Mantovani A (2012) Orchestration of metabolism by macrophages. Cell Metab 15(4):432–437.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Ribas C, Penela P, Murga C, Salcedo A, Garcia-Hoz C, Jurado-Pueyo M, Aymerich I, Mayor F Jr (2007) The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling. Biochem Biophys Acta 1768(4):913–922.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Hullmann J, Traynham CJ, Coleman RC, Koch WJ (2016) The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development. Pharmacol Res 110:52–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Penela P, Lafarga V, Tapia O, Rivas V, Nogues L, Lucas E, Vila-Bedmar R, Murga C, Mayor F Jr (2012) Roles of GRK2 in cell signaling beyond GPCR desensitization GRK2HDAC6 interaction modulates cell spreading and motility. Sci Signal 5(224):9–10.

    CAS  Article  Google Scholar 

  24. 24.

    Penela P, Murga C, Ribas C, Lafarga V, Mayor F Jr (2010) The complex G protein-coupled receptor kinase 2 (GRK2) interactome unveils new physiopathological targets. Br J Pharmacol 160(4):821–832.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Anis Y, Leshem O, Reuveni H, Wexler I, Ben Sasson R, Yahalom B, Laster M, Raz I, Ben Sasson S, Shafrir E, Ziv E (2004) Antidiabetic effect of novel modulating peptides of G-protein-coupled kinase in experimental models of diabetes. Diabetologia 47(7):1232–1244.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Mayor F Jr, Lucas E, Jurado-Pueyo M, Garcia-Guerra L, Nieto-Vazquez I, Vila-Bedmar R, Fernandez-Veledo S, Murga C (2011) G Protein-coupled receptor kinase 2 (GRK2): a novel modulator of insulin resistance. Arch Physiol Biochem 117(3):125–130.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Ciccarelli M, Cipolletta E, Iaccarino G (2012) GRK2 at the control shaft of cellular metabolism. Curr Pharm Des 18(2):121–127

    CAS  Article  Google Scholar 

  28. 28.

    Fan J, Malik AB (2003) Toll-like receptor-4 (TLR4) signaling augments chemokine-induced neutrophil migration by modulating cell surface expression of chemokine receptors. Nat Med 9(3):315–321.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Loniewski K, Shi Y, Pestka J, Parameswaran N (2008) Toll-like receptors differentially regulate GPCR kinases and arrestins in primary macrophages. Mol Immunol 45(8):2312–2322.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Lombardi MS, Kavelaars A, Penela P, Scholtens EJ, Roccio M, Schmidt RE, Schedlowski M, Mayor F Jr, Heijnen CJ (2002) Oxidative stress decreases G protein-coupled receptor kinase 2 in lymphocytes via a calpain-dependent mechanism. Mol Pharmacol 62(2):379–388

    CAS  Article  Google Scholar 

  31. 31.

    Vroon A, Heijnen CJ, Kavelaars A (2006) GRKs and arrestins: regulators of migration and inflammation. J Leukoc Biol 80(6):1214–1221.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Clausen BE, Burkhardt C, Reith W, Renkawitz R, Forster I (1999) Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgen Res 8(4):265–277

    CAS  Article  Google Scholar 

  33. 33.

    Willemen HL, Eijkelkamp N, Wang H, Dantzer R, Dorn GW 2nd, Kelley KW, Heijnen CJ, Kavelaars A (2010) Microglial/macrophage GRK2 determines duration of peripheral IL-1beta-induced hyperalgesia: contribution of spinal cord CX3CR1, p38 and IL-1 signaling. Pain 150(3):550–560.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Rivas V, Carmona R, Munoz-Chapuli R, Mendiola M, Nogues L, Reglero C, Miguel-Martin M, Garcia-Escudero R, Dorn GW 2nd, Hardisson D, Mayor F Jr, Penela P (2013) Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2. J Clin Investig 123(11):4714–4730.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Vila-Bedmar R, Cruces-Sande M, Lucas E, Willemen HL, Heijnen CJ, Kavelaars A, Mayor F, Murga C (2015) Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2. Science Signal 8(386):9–10.

    CAS  Article  Google Scholar 

  36. 36.

    Cruces-Sande M, Vila-Bedmar R, Arcones AC, Gonzalez-Rodriguez A, Rada P, Gutierrez-de-Juan V, Vargas-Castrillon J, Iruzubieta P, Sanchez-Gonzalez C, Formentini L, Crespo J, Garcia-Monzon C, Martinez-Chantar ML, Valverde AM, Mayor F Jr (1864) Murga C (2018) Involvement of G protein-coupled receptor kinase 2 (GRK2) in the development of non-alcoholic steatosis and steatohepatitis in mice and humans. Biochim Biophys Acta Mol Basis Dis 12:3655–3667.

    CAS  Article  Google Scholar 

  37. 37.

    Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJA, Holmes SP (2016) DADA2: high resolution sample inference from Illumina amplicon data. Nat Methods 13(7):581–583.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Bolyen ERJ, Dillon MR, Bokulich NA, Abnet C, Al-Ghalith GA, Alexander H, Alm EJ, Arumugam M, Asnicar F, Bai Y, Bisanz JE, Bittinger K, Brejnrod A, Brislawn CJ, Brown CT, Callahan BJ, Caraballo-Rodríguez AM, Chase J, Cope E, Da Silva R, Dorrestein PC, Douglas GM, Durall DM, Duvallet C, Edwardson CF, Ernst M, Estaki M, Fouquier J, Gauglitz JM, Gibson DL, Gonzalez A, Gorlick K, Guo J, Hillmann B, Holmes S, Holste H, Huttenhower C, Huttley G, Janssen S, Jarmusch AK, Jiang L, Kaehler B, Kang KB, Keefe CR, Keim P, Kelley ST, Knights D, Koester I, Kosciolek T, Kreps J, Langille MG, Lee J, Ley R, Liu Y, Loftfield E, Lozupone C, Maher M, Marotz C, Martin BD, McDonald D, McIver LJ, Melnik AV, Metcalf JL, Morgan SC, Morton J, Naimey AT, Navas-Molina JA, Nothias LF, Orchanian SB, Pearson T, Peoples SL, Petras D, Preuss ML, Pruesse E, Rasmussen LB, Rivers A, Robeson MS II, Rosenthal P, Segata N, Shaffer M, Shiffer A, Sinha R, Song SJ, Spear JR, Swafford AD, Thompson LR, Torres PJ, Trinh P, Tripathi A, Turnbaugh PJ, Ul-Hasan S, van der Hooft JJ, Vargas F, Vázquez-Baeza Y, Vogtmann E, von Hippel M, Walters W, Wan Y, Wang M, Warren J, Weber KC, Williamson CH, Willis AD, Xu ZZ, Zaneveld JR, Zhang Y, Zhu Q, Knight R, Caporaso JG (2018) QIIME 2: Reproducible, interactive, scalable, and extensible microbiome data science. PeerJ Prepr 6:27292–27295.

    Article  Google Scholar 

  39. 39.

    Rognes T, Flouri T, Nichols B, Quince C, Mahé F (2016) VSEARCH: a versatile open source tool for metagenomics. PeerJ 4:e2584.

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Mandal S, Van Treuren W, White RA, Eggesbø M, Knight R, Peddada SD (2015) Analysis of composition of microbiomes: a novel method for studying microbial composition. Microb Ecol Health Dis 26(1):27663.

    Article  PubMed  Google Scholar 

  41. 41.

    Maganto-Garcia E, Punzon C, Terhorst C, Fresno M (2008) Rab5 activation by Toll-like receptor 2 is required for Trypanosoma cruzi internalization and replication in macrophages. Traffic 9(8):1299–1315.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Vila-Bedmar R, Garcia-Guerra L, Nieto-Vazquez I, Mayor F Jr, Lorenzo M, Murga C, Fernandez-Veledo S (2012) GRK2 contribution to the regulation of energy expenditure and brown fat function. FASEB J 26(8):3503–3514.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Vila-Bedmar R, Lorenzo M, Fernandez-Veledo S (2010) Adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin cross talk regulates brown adipocyte differentiation. Endocrinology 151(3):980–992.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Hatting M, Tavares CDJ, Sharabi K, Rines AK, Puigserver P (2018) Insulin regulation of gluconeogenesis. Ann N Y Acad Sci 1411(1):21–35.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11(2):183–190.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Wan X, Xu C, Yu C, Li Y (2016) Role of NLRP3 Inflammasome in the Progression of NAFLD to NASH. Can J Gastroenterol Hepatol 2016:6489012.

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Hersoug LG, Moller P, Loft S (2016) Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity. Obesity Rev 17(4):297–312.

    CAS  Article  Google Scholar 

  48. 48.

    Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI (2005) Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 102(31):11070–11075.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Moran-Salvador E, Lopez-Parra M, Garcia-Alonso V, Titos E, Martinez-Clemente M, Gonzalez-Periz A, Lopez-Vicario C, Barak Y, Arroyo V, Claria J (2011) Role for PPARgamma in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J 25(8):2538–2550.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF, Burcelin R, Alessi MC (2007) C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50(6):1267–1276.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Bronsart LL, Contag CH (2016) A role of the adaptive immune system in glucose homeostasis. BMJ Open Diabetes Res Care 4(1):e000136.

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Bruun JM, Helge JW, Richelsen B, Stallknecht B (2006) Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects. Am J Physiol Endocrinol Metab 290(5):E961–967.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, Kahn CR (2003) Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Investig 112(4):608–618.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Stanton MC, Chen SC, Jackson JV, Rojas-Triana A, Kinsley D, Cui L, Fine JS, Greenfeder S, Bober LA, Jenh CH (2011) Inflammatory Signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice. J Inflamm (Lond) 8:8.

    CAS  Article  Google Scholar 

  55. 55.

    Lefere S, Tacke F (2019) Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism. JHEP Rep 1(1):30–43.

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Bijnen M, Josefs T, Cuijpers I, Maalsen CJ, van de Gaar J, Vroomen M, Wijnands E, Rensen SS, Greve JWM, Hofker MH, Biessen EAL, Stehouwer CDA, Schalkwijk CG, Wouters K (2018) Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice. Gut 67(7):1317–1327.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Rytka JM, Wueest S, Schoenle EJ, Konrad D (2011) The portal theory supported by venous drainage-selective fat transplantation. Diabetes 60(1):56–63.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, Barrett T, Kim JK, Davis RJ (2008) A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322(5907):1539–1543.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Wueest S, Rapold RA, Schumann DM, Rytka JM, Schildknecht A, Nov O, Chervonsky AV, Rudich A, Schoenle EJ, Donath MY, Konrad D (2010) Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. J Clin Investig 120(1):191–202.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Rosso C, Kazankov K, Younes R, Esmaili S, Marietti M, Sacco M, Carli F, Gaggini M, Salomone F, Moller HJ, Abate ML, Vilstrup H, Gastaldelli A, George J, Gronbaek H, Bugianesi E (2019) Crosstalk between adipose tissue insulin resistance and liver macrophages in non-alcoholic fatty liver disease. J Hepatol 71(5):1012–1021.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Andersson CX, Gustafson B, Hammarstedt A, Hedjazifar S, Smith U (2008) Inflamed adipose tissue, insulin resistance and vascular injury. Diabetes Metab Res Rev 24(8):595–603.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Fruhbeck G, Catalan V, Rodriguez A, Gomez-Ambrosi J (2018) Adiponectin-leptin ratio: a promising index to estimate adipose tissue dysfunction. Relation with obesity-associated cardiometabolic risk. Adipocyte 7(1):57–62.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Investig 116(7):1784–1792.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Combs TP, Marliss EB (2014) Adiponectin signaling in the liver. Rev Endocr Metab Disord 15(2):137–147.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Gustafson B, Hammarstedt A, Andersson CX, Smith U (2007) Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol 27(11):2276–2283.

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Gustafson B (2010) Adipose tissue, inflammation and atherosclerosis. J Atheroscler Thromb 17(4):332–341

    CAS  Article  Google Scholar 

  67. 67.

    Liu Z, Jiang Y, Li Y, Wang J, Fan L, Scott MJ, Xiao G, Li S, Billiar TR, Wilson MA, Fan J (2013) TLR4 Signaling augments monocyte chemotaxis by regulating G protein-coupled receptor kinase 2 translocation. J Immunol 191(2):857–864.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Arnon TI, Xu Y, Lo C, Pham T, An J, Coughlin S, Dorn GW, Cyster JG (2011) GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood. Science 333(6051):1898–1903.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Penela P, Ribas C, Aymerich I, Eijkelkamp N, Barreiro O, Heijnen CJ, Kavelaars A, Sanchez-Madrid F, Mayor F Jr (2008) G protein-coupled receptor kinase 2 positively regulates epithelial cell migration. EMBO J 27(8):1206–1218.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Grisanti LA, Traynham CJ, Repas AA, Gao E, Koch WJ, Tilley DG (2016) beta2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury. Proc Natl Acad Sci USA 113(52):15126–15131.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Parker R, Weston CJ, Miao Z, Corbett C, Armstrong MJ, Ertl L, Ebsworth K, Walters MJ, Baumart T, Newland D, McMahon J, Zhang P, Singh R, Campbell J, Newsome PN, Charo I, Schall TJ, Adams DH (2018) CC chemokine receptor 2 promotes recruitment of myeloid cells associated with insulin resistance in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 314(4):G483–G493.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Ashino T, Yamanaka R, Yamamoto M, Shimokawa H, Sekikawa K, Iwakura Y, Shioda S, Numazawa S, Yoshida T (2008) Negative feedback regulation of lipopolysaccharide-induced inducible nitric oxide synthase gene expression by heme oxygenase-1 induction in macrophages. Mol Immunol 45(7):2106–2115.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. J Clin Investig 107(1):7–11.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Rajakariar R, Yaqoob MM, Gilroy DW (2006) COX-2 in inflammation and resolution. Mol Interv 6(4):199–207.

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA (1999) Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med 5(6):698–701.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Gao Y, Zhang H, Luo L, Lin J, Li D, Zheng S, Huang H, Yan S, Yang J, Hao Y, Li H, Gao Smith F, Jin S (2017) Resolvin D1 Improves the Resolution of Inflammation via Activating NF-kappaB p50/p50-Mediated Cyclooxygenase-2 Expression in Acute Respiratory Distress Syndrome. J Immunol.

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Scher JU, Pillinger MH (2005) 15d-PGJ2: the anti-inflammatory prostaglandin? Clin Immunol 114(2):100–109.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Tsoyi K, Ha YM, Kim YM, Lee YS, Kim HJ, Kim HJ, Seo HG, Lee JH, Chang KC (2009) Activation of PPAR-gamma by carbon monoxide from CORM-2 leads to the inhibition of iNOS but not COX-2 expression in LPS-stimulated macrophages. Inflammation 32(6):364–371.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Han Z, Zhu T, Liu X, Li C, Yue S, Liu X, Yang L, Yang L, Li L (2012) 15-deoxy-Delta 12,14 -prostaglandin J2 reduces recruitment of bone marrow-derived monocyte/macrophages in chronic liver injury in mice. Hepatology 56(1):350–360.

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Takayama K, Garcia-Cardena G, Sukhova GK, Comander J, Gimbrone MA Jr, Libby P (2002) Prostaglandin E2 suppresses chemokine production in human macrophages through the EP4 receptor. J Biolog Chem 277(46):44147–44154.

    CAS  Article  Google Scholar 

  81. 81.

    Jia XY, Chang Y, Wei F, Dai X, Wu YJ, Sun XJ, Xu S, Wu HX, Wang C, Yang XZ, Wei W (2019) CP-25 reverses prostaglandin E4 receptor desensitization-induced fibroblast-like synoviocyte dysfunction via the G protein-coupled receptor kinase 2 in autoimmune arthritis. Acta Pharmacol Sin.

    Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Bacou E, Haurogne K, Allard M, Mignot G, Bach JM, Herve J, Lieubeau B (2017) beta2-adrenoreceptor stimulation dampens the LPS-induced M1 polarization in pig macrophages. Dev Comp Immunol 76:169–176.

    CAS  Article  PubMed  Google Scholar 

  83. 83.

    Grailer JJ, Haggadone MD, Sarma JV, Zetoune FS, Ward PA (2014) Induction of M2 regulatory macrophages through the beta2-adrenergic receptor with protection during endotoxemia and acute lung injury. J Innate Immun 6(5):607–618.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Keranen T, Hommo T, Moilanen E, Korhonen R (2017) beta2-receptor agonists salbutamol and terbutaline attenuated cytokine production by suppressing ERK pathway through cAMP in macrophages. Cytokine 94:1–7.

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Patial S, Saini Y, Parvataneni S, Appledorn DM, Dorn GW 2nd, Lapres JJ, Amalfitano A, Senagore P, Parameswaran N (2011) Myeloid-specific GPCR kinase-2 negatively regulates NF-kappaB1p105-ERK pathway and limits endotoxemic shock in mice. J Cell Physiol 226(3):627–637.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Peregrin S, Jurado-Pueyo M, Campos PM, Sanz-Moreno V, Ruiz-Gomez A, Crespo P, Mayor F Jr, Murga C (2018) Phosphorylation of p38 by GRK2 at the docking groove unveils a novel mechanism for inactivating p38MAPK. Curr Biol 28(15):2513.

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Willemen HL, Eijkelkamp N, Garza Carbajal A, Wang H, Mack M, Zijlstra J, Heijnen CJ, Kavelaars A (2014) Monocytes/macrophages control resolution of transient inflammatory pain. J Pain 15(5):496–506.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Patial S, Luo J, Porter KJ, Benovic JL, Parameswaran N (2009) G-protein-coupled-receptor kinases mediate TNFalpha-induced NFkappaB signalling via direct interaction with and phosphorylation of IkappaBalpha. Biochem J 425(1):169–178.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Palikhe S, Ohashi W, Sakamoto T, Hattori K, Kawakami M, Andoh T, Yamazaki H, Hattori Y (2019) Regulatory role of GRK2 in the TLR signaling-mediated iNOS induction pathway in microglial cells. Front Pharmacol 10:59.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Kawakami M, Hattori M, Ohashi W, Fujimori T, Hattori K, Takebe M, Tomita K, Yokoo H, Matsuda N, Yamazaki M, Hattori Y (2018) Role of G protein-coupled receptor kinase 2 in oxidative and nitrosative stress-related neurohistopathological changes in a mouse model of sepsis-associated encephalopathy. J Neurochem 145(6):474–488.

    CAS  Article  PubMed  Google Scholar 

Download references


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.

Author information



Corresponding authors

Correspondence to Federico Mayor Jr or Cristina Murga.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 753 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation


  • Obesity
  • Macrophages
  • GRK2
  • Liver
  • Adipose tissue
  • Glucose homeostasis