title: Glucose-dependent insulinotropic peptide impairs insulin signaling via inducing adipocyte inflammation in glucose-dependent insulinotropic peptide receptor-overexpressing adipocytes.
abstract: Glucose-dependent insulinotropic peptide (GIP) exerts multiple biological effects via the G-protein-coupled receptor GIPR, including glucose-stimulated insulin production and secretion, cell proliferation, and antiapoptosis in pancreatic β-cells. In an obese state, the circulating level of GIP is elevated. GIPR-knockout mice are resistant to high-fat-diet-induced obesity. The rising evidence suggests a potential role of GIP in adipocyte biology and lipid metabolism. In our study, we overexpressed GIPR in 3T3-L1 CAR adipocytes and demonstrated that GIP impaired the physiological functions of adipocytes as a consequence of increased production of inflammatory cytokines and chemokines and phosphorylation of IkB kinase (IKK)-β through activation of the cAMP-PKA pathway. Activation of Jun N-terminal kinase (JNK) pathway was also observed during GIP-induced inflammatory responses in adipocytes. The inhibition of JNK blocked GIP-stimulated secretion of inflammatory cytokines and chemokines, as well as phosphorylation of IKKβ. In addition, GIP-induced inflammatory response increased basal glucose uptake but inhibited insulin-stimulated glucose uptake. Moreover, GIP-induced adipocyte inflammation impaired insulin signaling in adipocytes as demonstrated by a reduction of AKT phosphorylation. Our results suggest that GIP might be one of the stimuli attributable to obesity-induced insulin resistance via the induction of adipocyte inflammation.
authors.affiliation: Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, China.
authors.forename: Yaohui
authors.initials: Y
authors.lastname: Nie
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Ma
authors.forename: Juliana C N
authors.initials: JC
authors.lastname: Chan
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology; D007328:Insulin / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011964:Receptors, Gastrointestinal Hormone / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D048670:MAP Kinase Kinase 4; D005947:Glucose