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Title: Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance.
Authors: Ceperuelo-Mallafré, Victoria
Durán, Xavier
Pachón, Gisela
Roche, Kelly
Garrido-Sánchez, Lourdes
Vilarrasa, Nuria
Tinahones, Francisco J
Vicente, Vicente
Pujol, Jordi
Vendrell, Joan
Fernández-Veledo, Sonia
metadata.dc.contributor.authoraffiliation: [Ceperuelo-Mallafré,V; Garrido-Sánchez,L; Tinahones,FJ] CIBERobn Instituto de Salud Carlos III, CIBER Fisiopatología de la Obesidad y de la Nutrición, Madrid, Spain. [Ceperuelo-Mallafré,V; Garrido-Sánchez,L; Tinahones,FJ] Hospital Universitario Virgen de la Victoria, Málaga, Spain. [Durán,X; Pachón,G; Roche,K; Vilarrasa,N; Vendrell,J; Fernández-Veledo, Sonia] CIBERDEM Instituto de Salud Carlos III, CIBER Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain. [Pachón,G; Roche,K; Vicente,V; Vendrell,J; Fernández-Veledo,S] Hospital Universitario de Tarragona Joan XXIII, Instituto de Investigación Sanitaria Pere Virgili, Universitat Rovira Virgili, Tarragona, Spain. [Vilarrasa,N; Pujol,Jordi] Hospital Universitario de Bellvitge, Barcelona, Spain.
Keywords: Tejido adiposo;Índice de masa corporal;Línea celular;Regulación hacia abajo;Polipéptido inhibidor gástrico;Resistencia a la insulina;Obesidad;Receptores de la hormona gastrointestinal;Transducción de señal;Circunferencia de la cintura;Adipocitos
metadata.dc.subject.mesh: Medical Subject Headings::Anatomy::Tissues::Connective Tissue::Adipose Tissue
Medical Subject Headings::Named Groups::Persons::Age Groups::Adult
Medical Subject Headings::Named Groups::Persons::Age Groups::Adult::Aged
Medical Subject Headings::Health Care::Environment and Public Health::Public Health::Epidemiologic Measurements::Biometry::Anthropometry::Body Mass Index
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Down-Regulation
Medical Subject Headings::Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gastrointestinal Hormones::Gastric Inhibitory Polypeptide
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin Resistance
Medical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Peptide::Receptors, Gastrointestinal Hormone
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction
Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Body Constitution::Body Weights and Measures::Body Size::Waist Circumference
Medical Subject Headings::Anatomy::Cells::Connective Tissue Cells::Adipocytes
Issue Date: May-2014
Publisher: Endocrine Society
Citation: Ceperuelo-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):E908-19
Abstract: 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.
Description: Journal Article; Research Support, Non-U.S. Gov't;
metadata.dc.identifier.doi: 10.1210/jc.2013-3350
ISSN: 1945-7197 (Online)
0021-972X (Print)
Appears in Collections:01- Artículos - Hospital Virgen de la Victoria

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