title: Interleukin-1beta may mediate insulin resistance in liver-derived cells in response to adipocyte inflammation.
abstract: Central obesity is frequently associated with adipose tissue inflammation and hepatic insulin resistance. To identify potential individual mediators in this process, we used in vitro systems and assessed if insulin resistance in liver cells could be induced by secreted products from adipocytes preexposed to an inflammatory stimulus. Conditioned medium from 3T3-L1 adipocytes pretreated without (CM) or with TNFalpha (CM-TNFalpha) was used to treat Fao hepatoma cells. ELISAs were used to assess the concentration of several inflammatory mediators in CM-TNFalpha. CM-TNFalpha-treated Fao cells exhibited about 45% diminution in insulin-stimulated phosphorylation of insulin receptor, insulin receptor substrate proteins, protein kinase B, and glycogen synthase kinase-3 as compared with CM-treated cells, without changes in the total abundance of these protein. Insulin increased glycogenesis by 2-fold in CM-treated Fao cells but not in cells exposed to CM-TNFalpha. Expression of IL-1beta mRNA was elevated 3-fold in TNFalpha-treated adipocytes, and CM-TNFalpha had 10-fold higher concentrations of IL-1beta but not TNFalpha or IL-1alpha. IL-1beta directly induced insulin resistance in Fao, HepG2, and in primary rat hepatocytes. Moreover, when TNFalpha-induced secretion/production of IL-1beta from adipocytes was inhibited by the IL-1 converting enzyme (ICE-1) inhibitor II (Ac-YVAD-CMK), insulin resistance was prevented. Furthermore, liver-derived cells treated with IL-1 receptor antagonist were protected against insulin resistance induced by CM-TNFalpha. Finally, IL-1beta secretion from human omental fat explants correlated with body mass index (R(2) = 0.639, P < 0.01), and the resulting CM induced insulin resistance in HepG2 cells, inhibitable by IL-1 receptor antagonist. Our results suggest that adipocyte-derived IL-1beta may constitute a mediator in the perturbed cross talk between adipocytes and liver cells in response to adipose tissue inflammation.
authors.affiliation: Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84103, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Nov
authors.forename: Ayelet
authors.initials: A
authors.lastname: Kohl
authors.forename: Eli C
authors.initials: EC
authors.lastname: Lewis
authors.forename: Nava
authors.initials: N
authors.lastname: Bashan
authors.forename: Irit
authors.initials: I
authors.lastname: Dvir
authors.forename: Shani
authors.initials: S
authors.lastname: Ben-Shlomo
authors.forename: Sigal
authors.initials: S
authors.lastname: Fishman
authors.forename: Stephan
authors.initials: S
authors.lastname: Wueest
authors.forename: Daniel
authors.initials: D
authors.lastname: Konrad
authors.forename: Assaf
authors.initials: A
authors.lastname: Rudich
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D053583:Interleukin-1beta / Q000235:genetics / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017077:Culture Media, Conditioned; D007004:Hypoglycemic Agents; D007328:Insulin; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha