Victòria Ceperuelo-Mallafré1, Xavier Duran, Gisela Pachón, Kelly Roche, Lourdes Garrido-Sánchez, Nuria Vilarrasa, Francisco J Tinahones, Vicente Vicente, Jordi Pujol, Joan Vendrell, Sonia Fernández-Veledo. 1. 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.
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.
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 obesepatients. RESULTS:GIPR expression was downregulated in SAT from obesepatients 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: J Góralska; U Raźny; A Polus; J Stancel-Możwiłło; M Chojnacka; A Gruca; A Zdzienicka; A Dembińska-Kieć; B Kieć-Wilk; B Solnica; M Malczewska-Malec Journal: Int J Obes (Lond) Date: 2017-12-13 Impact factor: 5.095
Authors: Jonathan E Campbell; Jacqueline L Beaudry; Berit Svendsen; Laurie L Baggio; Andrew N Gordon; John R Ussher; Chi Kin Wong; Fiona M Gribble; David A D'Alessio; Frank Reimann; Daniel J Drucker Journal: Diabetes Date: 2022-05-01 Impact factor: 9.337
Authors: Urszula Razny; Beata Kiec-Wilk; Anna Polus; Joanna Goralska; Malgorzata Malczewska-Malec; Dominika Wnek; Anna Zdzienicka; Anna Gruca; Caroline E Childs; Maria Kapusta; Krystyna Slowinska-Solnica; Philip C Calder; Aldona Dembinska-Kiec Journal: BBA Clin Date: 2015-05-22