title: Both inflammatory and classical lipolytic pathways are involved in lipopolysaccharide-induced lipolysis in human adipocytes.
abstract: High fat diet-induced endotoxaemia triggers low-grade inflammation and lipid release from adipose tissue. This study aims to unravel the cellular mechanisms leading to the lipopolysaccharide (LPS) effects in human adipocytes. Subcutaneous pre-adipocytes surgically isolated from patients were differentiated into mature adipocytes in vitro. Lipolysis was assessed by measurement of glycerol release and mRNA expression of pro-inflammatory cytokines were evaluated by real-time PCR. Treatment with LPS for 24 h induced a dose-dependent increase in interleukin (IL)-6 and IL-8 mRNA expression. At 1 µg/ml LPS, IL-6 and IL-8 were induced to 19.5 ± 1.8-fold and 662.7 ± 91.5-fold (P < 0.01 vs basal), respectively. From 100 ng/ml to 1 µg/ml, LPS-induced lipolysis increased to a plateau of 3.1-fold above basal level (P < 0.001 vs basal). Co-treatment with inhibitors of inhibitory kappa B kinase kinase beta (IKKβ) or NF-κB inhibited LPS-induced glycerol release. Co-treatment with the protein kinase A (PKA) inhibitor H-89, the lipase inhibitor orlistat or the hormone-sensitive lipase (HSL) inhibitor CAY10499 abolished the lipolytic effects of LPS. Co-treatment with the MAPK inhibitor, U0126 also reduced LPS-induced glycerol release. Inhibition of lipolysis by orlistat or CAY10499 reduced LPS-induced IL-6 and IL-8 mRNA expression. Induction of lipolysis by the synthetic catecholamine isoproterenol or the phosphodiesterase type III inhibitor milrinone did not alter basal IL-6 and IL-8 mRNA expression after 24 treatments whereas these compounds enhanced LPS-induced IL-6 and IL-8 mRNA expression. Both the inflammatory IKKβ/NF-κB pathway and the lipolytic PKA/HSL pathways mediate LPS-induced lipolysis. In turn, LPS-induced lipolysis reinforces the expression of pro-inflammatory cytokines and, thereby, triggers its own lipolytic activity.
authors.affiliation: Department of Biomedicine, Metabolism Group, University Hospital Basel, Basel, Switzerland. jean.grisouard@unibas.ch
authors.forename: Jean
authors.initials: J
authors.lastname: Grisouard
authors.forename: Elisa
authors.initials: E
authors.lastname: Bouillet
authors.forename: Katharina
authors.initials: K
authors.lastname: Timper
authors.forename: Tanja
authors.initials: T
authors.lastname: Radimerski
authors.forename: Kaethi
authors.initials: K
authors.lastname: Dembinski
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Frey
authors.forename: Ralph
authors.initials: R
authors.lastname: Peterli
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 / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*
chemical_list: D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D051550:I-kappa B Kinase; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D005990:Glycerol