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 TNFα (CM-TNFα) was used to treat Fao hepatoma cells. ELISAs were used to assess the concentration of several inflammatory mediators inCM-TNFα.CM-TNFα-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-TNFα. Expression of IL-1β mRNA was elevated 3-fold in TNFα-treated adipocytes, and CM-TNFα had 10-fold higher concentrations of IL-1β but not TNFα or IL-1β. IL-1β directly induced insulin resistance in Fao, HepG2, and in primary rat hepatocytes. Moreover, when TNFα-induced secretion/production of IL-1β 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-TNFα. Finally, IL-1β secretion from human omental fat explants correlated with body mass index (R2 = 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-1β may constitute a mediator in the perturbed cross talk between adipocytes and liver cells in response to adipose tissue inflammation.
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