Ceperuelo-Mallafré, VictoriaDurán, XavierPachón, GiselaRoche, KellyGarrido-Sánchez, LourdesVilarrasa, NuriaTinahones, Francisco JVicente, VicentePujol, JordiVendrell, JoanFernández-Veledo, Sonia2015-11-132015-11-132014-05Ceperuelo-Mallafré V, Duran X, Pachón G, Roche K, Garrido-Sánchez L, Vilarrasa N, et al. Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance. J. Clin. Endocrinol. Metab.. 2014; 99(5):E908-190021-972Xhttp://hdl.handle.net/10668/2050Journal Article; Research Support, Non-U.S. Gov't;CONTEXT Glucose-dependent insulinotropic peptide (GIP) has a central role in glucose homeostasis through its amplification of insulin secretion; however, its physiological role in adipose tissue is unclear. OBJECTIVE Our objective was to define the function of GIP in human adipose tissue in relation to obesity and insulin resistance. DESIGN GIP receptor (GIPR) expression was analyzed in human sc adipose tissue (SAT) and visceral adipose (VAT) from lean and obese subjects in 3 independent cohorts. GIPR expression was associated with anthropometric and biochemical variables. GIP responsiveness on insulin sensitivity was analyzed in human adipocyte cell lines in normoxic and hypoxic environments as well as in adipose-derived stem cells obtained from lean and obese patients. RESULTS GIPR expression was downregulated in SAT from obese patients and correlated negatively with body mass index, waist circumference, systolic blood pressure, and glucose and triglyceride levels. Furthermore, homeostasis model assessment of insulin resistance, glucose, and G protein-coupled receptor kinase 2 (GRK2) emerged as variables strongly associated with GIPR expression in SAT. Glucose uptake studies and insulin signaling in human adipocytes revealed GIP as an insulin-sensitizer incretin. Immunoprecipitation experiments suggested that GIP promotes the interaction of GRK2 with GIPR and decreases the association of GRK2 to insulin receptor substrate 1. These effects of GIP observed under normoxia were lost in human fat cells cultured in hypoxia. In support of this, GIP increased insulin sensitivity in human adipose-derived stem cells from lean patients. GIP also induced GIPR expression, which was concomitant with a downregulation of the incretin-degrading enzyme dipeptidyl peptidase 4. None of the physiological effects of GIP were detected in human fat cells obtained from an obese environment with reduced levels of GIPR. CONCLUSIONS GIP/GIPR signaling is disrupted in insulin-resistant states, such as obesity, and normalizing this function might represent a potential therapy in the treatment of obesity-associated metabolic disorders.enTejido adiposoÍndice de masa corporalLínea celularRegulación hacia abajoPolipéptido inhibidor gástricoResistencia a la insulinaObesidadReceptores de la hormona gastrointestinalTransducción de señalCircunferencia de la cinturaAdipocitosMedical Subject Headings::Anatomy::Tissues::Connective Tissue::Adipose TissueMedical Subject Headings::Named Groups::Persons::Age Groups::AdultMedical Subject Headings::Named Groups::Persons::Age Groups::Adult::AgedMedical Subject Headings::Health Care::Environment and Public Health::Public Health::Epidemiologic Measurements::Biometry::Anthropometry::Body Mass IndexMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell LineMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-RegulationMedical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gastrointestinal Hormones::Gastric Inhibitory PolypeptideMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin ResistanceMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::ObesityMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Peptide::Receptors, Gastrointestinal HormoneMedical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal TransductionMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::Body Constitution::Body Weights and Measures::Body Size::Waist CircumferenceMedical Subject Headings::Anatomy::Cells::Connective Tissue Cells::Adipocytesresearch article24512489open access10.1210/jc.2013-33501945-7197