title: Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2.
abstract: Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance. To support GRK2 as a potential drug target in type 2 diabetes and obesity, we investigated whether lowering GRK2 abundance reversed an ongoing systemic insulin-resistant phenotype, using a mouse model of tamoxifen-induced GRK2 ablation after high-fat diet-dependent obesity and insulin resistance. Tamoxifen-triggered GRK2 deletion impeded further body weight gain, normalized fasting glycemia, improved glucose tolerance, and was associated with preserved insulin sensitivity in skeletal muscle and liver, thereby maintaining whole-body glucose homeostasis. Moreover, when continued to be fed a high-fat diet, these animals displayed reduced fat mass and smaller adipocytes, were resistant to the development of liver steatosis, and showed reduced expression of proinflammatory markers in the liver. Our results indicate that GRK2 acts as a hub to control metabolic functions in different tissues, which is key to controlling insulin resistance development in vivo. These data suggest that inhibiting GRK2 could reverse an established insulin-resistant and obese phenotype, thereby putting forward this enzyme as a potential therapeutic target linking glucose homeostasis and regulation of adiposity.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Vila-Bedmar
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cruces-Sande
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Lucas
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht 3584 EA, Netherlands.
authors.forename: Hanneke L D M
authors.initials: HL
authors.lastname: Willemen
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht 3584 EA, Netherlands. Laboratory of Neuroimmunology, Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht 3584 EA, Netherlands. Laboratory of Neuroimmunology, Division of Internal Medicine, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain. cmurga@cbm.csic.es fmayor@cbm.csic.es.
authors.forename: Federico
authors.initials: F
authors.lastname: Mayor
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid 28049, Spain. Instituto de Investigación Sanitaria La Princesa, Madrid 28006, Spain. cmurga@cbm.csic.es fmayor@cbm.csic.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Murga
mesh_terms: D050154:Adiposity; D000818:Animals; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D005947:Glucose