Abstract 18508: Exposure of Adipocytes to High Mobility Group Box 1 Impairs Insulin Signaling via RAGE, While Stimulating Monocyte Recruitment Through TLR2
Background: Smokers show increased prevalence of insulin resistance for glucose and type 2 diabetes mellitus (T2DM). The underlying mechanisms, however, remain poorly understood. Tobacco smoke exposure increases tissue expression of high mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) that activates innate immunity. We recently reported that exposure of human macrophages to tobacco smoke extract (TSE) provokes the release of HMGB1 in two forms: as a soluble molecule and carried on membrane microvesicles (MV). Both soluble recombinant HMGB1 (rHMGB1) and MV-associated HMGB1 on TSE-induced MVs (TSE-MVs) mediate crucial crosstalk with adipocytes by impairing insulin signaling and by recruiting monocytes to the adipocytes -
GOAL- To identify the receptors on adipocytes that mediate the effects of HMGB1 on insulin signaling and monocyte recruitment.
Methods: Cultured 3T3-L1 adipocytes were incubated for 24h with rHMGB1 or TSE-MVs, in the absence or presence of neutralizing antibodies against different receptors, followed by assays of signaling responses to insulin and chemoattraction of monocytes across a Boyden chamber.
Results: Exposure of adipocytes to rHMGB1 or TSE-MVs impaired insulin-induced phosphorylations of IRS1 (Tyr612) and AKT (Ser473) and induced MCP1 secretion and hence monocyte transmigration and adherence to the cultured adipocytes. Neutralizing antibodies against RAGE, but not TLR2, improved insulin signaling in adipocytes exposed to rHMGB1 or TSE-MVs. In contrast, neutralizing antibodies against TLR2, but not RAGE, attenuated the induction of MCP1 secretion, and hence inhibited monocyte transmigration and adherence to cultured adipocytes exposed to rHMGB1 or TSE-MV.
Conclusion: Our results indicate that soluble and MV-associated HMGB1 that is released from macrophages exposed to tobacco smoke mediates harmful macrophage-adipocyte crosstalk through two pathways: via adipocyte RAGE to impair insulin signaling, and via adipocyte TLR2 to induce MCP1 secretion and monocyte recruitment. These pathways may contribute to insulin resistance for glucose and the development of T2DM in individuals exposed to tobacco smoke.
- © 2013 by American Heart Association, Inc.