title: Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors: CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBERobn-Instituto de Salud Carlos III, 28029 Madrid, Spain) and Hospital Universitario Virgen de la Victoria (V.C.-M., L.G.-S., F.J.T.), 29010 Málaga, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM-Instituto de Salud Carlos III, 28029 Madrid, Spain) (X.D., G.P., K.R., N.V., J.V., S.F.-V.) and Hospital Universitari de Tarragona Joan XXIII-Institut d Investigació Sanitária Pere Virgili-Universitat Rovira i Virgili (G.P., K.R., V.V., J.V., S.F.-V.), 43007 Tarragona, Spain; and Hospital Universitari de Bellvitge (N.V., J.P.), 08907 Barcelona, Spain.
authors: Victòria
authors: V
authors: Ceperuelo-Mallafré
authors: Xavier
authors: X
authors: Duran
authors: Gisela
authors: G
authors: Pachón
authors: Kelly
authors: K
authors: Roche
authors: Lourdes
authors: L
authors: Garrido-Sánchez
authors: Nuria
authors: N
authors: Vilarrasa
authors: Francisco J
authors: FJ
authors: Tinahones
authors: Vicente
authors: V
authors: Vicente
authors: Jordi
authors: J
authors: Pujol
authors: Joan
authors: J
authors: Vendrell
authors: Sonia
authors: S
authors: Fernández-Veledo
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000368:Aged; D015992:Body Mass Index; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D055105:Waist Circumference
chemical_list: D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor