title: Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis, and insulin resistance in human adipocytes.
abstract: Obesity-related insulin resistance is linked to a chronic state of systemic and adipose tissue-derived inflammation. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone also acting on adipocytes. We investigated whether GIP affects inflammation, lipolysis, and insulin resistance in human adipocytes. Human subcutaneous preadipocyte-derived adipocytes, differentiated in vitro, were treated with human GIP to analyze mRNA expression and protein secretion of cytokines, glycerol, and free fatty acid release and insulin-induced glucose uptake. GIP induced mRNA expression of IL-6, IL-1β, and the IL-1 receptor antagonist IL-1Ra, whereas TNFα, IL-8, and monocyte chemotactic protein (MCP)-1 remained unchanged. Cytokine induction involved PKA and the NF-κB pathway as well as an autocrine IL-1 effect. Furthermore, GIP potentiated IL-6 and IL-1Ra secretion in the presence of LPS, IL-1β, and TNFα. GIP induced lipolysis via activation of hormone-sensitive lipase and was linked to NF-κB activation. Finally, chronic GIP treatment impaired insulin-induced glucose uptake possibly due to the observed impaired translocation of glucose transporter GLUT4. In conclusion, GIP induces an inflammatory and prolipolytic response via the PKA -NF-κB-IL-1 pathway and impairs insulin sensitivity of glucose uptake in human adipocytes.
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland. timperk@uhbs.ch
authors.forename: Katharina
authors.initials: K
authors.lastname: Timper
authors.forename: Jean
authors.initials: J
authors.lastname: Grisouard
authors.forename: Nadine S
authors.initials: NS
authors.lastname: Sauter
authors.forename: Tanja
authors.initials: T
authors.lastname: Herzog-Radimerski
authors.forename: Kaethi
authors.initials: K
authors.lastname: Dembinski
authors.forename: Ralph
authors.initials: R
authors.lastname: Peterli
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Frey
authors.forename: Henryk
authors.initials: H
authors.lastname: Zulewski
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
authors.forename: Beat
authors.initials: B
authors.lastname: Müller
authors.forename: Mirjam
authors.initials: M
authors.lastname: Christ-Crain
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D019440:Anti-Obesity Agents / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects* / Q000235:genetics; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D000077403:Orlistat; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D019440:Anti-Obesity Agents; D016207:Cytokines; C508585:IL1B protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D007783:Lactones; D016328:NF-kappa B; D005749:Gastric Inhibitory Polypeptide; D000077403:Orlistat; D017868:Cyclic AMP-Dependent Protein Kinases