title: A naturally occurring GIP receptor variant undergoes enhanced agonist-induced desensitization, which impairs GIP control of adipose insulin sensitivity.
abstract: Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone secreted from gastrointestinal K cells in response to food intake, has an important role in the control of whole-body metabolism. GIP signals through activation of the GIP receptor (GIPR), a G-protein-coupled receptor (GPCR). Dysregulation of this pathway has been implicated in the development of metabolic disease. Here we demonstrate that GIPR is constitutively trafficked between the plasma membrane and intracellular compartments of both GIP-stimulated and unstimulated adipocytes. GIP induces a downregulation of plasma membrane GIPR by slowing GIPR recycling without affecting internalization kinetics. This transient reduction in the expression of GIPR in the plasma membrane correlates with desensitization to the effects of GIP. A naturally occurring variant of GIPR (E354Q) associated with an increased incidence of insulin resistance, type 2 diabetes, and cardiovascular disease in humans responds to GIP stimulation with an exaggerated downregulation from the plasma membrane and a delayed recovery of GIP sensitivity following cessation of GIP stimulation. This perturbation in the desensitization-resensitization cycle of the GIPR variant, revealed in studies of cultured adipocytes, may contribute to the link of the E354Q variant to metabolic disease.
authors.affiliation: Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Mohammad
authors.affiliation: Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Rajesh T
authors.initials: RT
authors.lastname: Patel
authors.affiliation: Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA Weill Cornell Medical College, Rockefeller University, and Memorial Sloan-Kettering Cancer Center Tri-Institutional MD-PhD Program, New York, New York, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Bruno
authors.affiliation: Medical Program, Weill Cornell Medical College in Qatar, Education City, Doha, Qatar.
authors.forename: Muhammad Siyab
authors.initials: MS
authors.lastname: Panhwar
authors.affiliation: Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, New York, New York, USA temcgraw@med.cornell.edu.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: McGraw
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006056:Golgi Apparatus / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D021381:Protein Transport; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor