The Role Of Preadipokine In Chronic Inflammation Underlying Insulin Resistance And The Antiinflammatory Actions Of GLP-1

Chronic inflammation in adipose tissue plays a key role in thedevelopment of insulin resistance. However, the underlying mechanismsleading to adipose tissue inflammation are largely unknown. Preadipokinesare proteins specifically secreted by preadipocytes and exert proinflammatoryactivities. Nevertheless, the relationship between preadipokines and adiposetissue inflammation and insulin resistance is little known. Additionally，inspite of the essentical role of chronic inflammation in insulin resistance,current anti-inflammatory treatments are not efficient in improving insulinresistance. Thus, novel anti-inflammatory treatments are required toameliorate insulin resistance. In this study, we investigated the relationshipbetween preadipokines and obesity, as well as their roles in adipose tissueinflammation and insulin resistance. In addition, we also determined theanti-inflammatory actions of GLP-1.1. The Inflammatory Properties of PreadipocytesObjective: to investigate the inflammatory properties of preadipocytes andtheir interactions with macrophages. Methods: the expression of inflammatory mediators in3T3-L1preadipocytesand mature adipocytes were evaluated by quantatitive PCR; The effects ofmacrophage-conditioned medium on inflammatory mediator expression inpreadipocytes were also determined. In addition, the chemoattractantactivities of conditioned medium from preadipocytes were assessed bytranswell migration assay.Results: The expression of inflammatory mediators including IL-6, MCP-1and RANTES was significantly higher in3T3-L1preadipocytes than inmature adipocytes. In addition, conditioned medium from macrophagesmarkedly induced the expression of above inflammatory mediators inpreadipocytes. Moreover, preadipocyte-conditioned medium promoted themigration of macrophages.Conclusion: Compared with mature adipocytes, preadipocytes possess moreobvious inflammatory characteristics. Furthermore, preadipocytes caninteract with macrophages and aggaravate inflammatory responses.2. The Association of Preadipokine FSTL1with Obesity and Its Role inthe Development of Adipose Tissue Inflammation and Insulin Resistance.Objective: to investigate the association of novel preadipokine FSTL1withobesity and its effects on adipose tissue inflammation and insulin sensitivity.Methods: the expression of FSTL1during3T3-L1preadipocytedifferentiation and its regulation by inflammatory cytokines was determinedby quantitive PCR and Western blot analysis. FSTL1levels in adipose tissueof obese mice and in serum of obese humans were also examined.Furthermore, the proinflammatory effects of FSTL1on adipocytes andmacrophages were investigated via in vitro experiments. Finally, the impacts of FSTL1on insulin sensitivity of adipocytes were also determined.Results: the expression of FSTL1markedly declined during thedifferentiation of3T3-L1preadipocytes, while TNFα re-induced FSTL1expression in mature adipocytes. In vivo, FSTL1expression was markedlyincreased in adipose tissues of both genetically and diet-induced obese micecompared with lean mice. Moreover, serum levels of FSTL1weresignificantly higher in obese humans than in control subjects, and werepositively correlated with BMI. In vitro experiments further revealed thatrecombinant FSTL1activated the IKKβ-NFκB and JNK signaling pathwaysin both adipocytes and macrophages, and induced the expression ofinflammatory cytokines including TNFα、IL-6and MCP-1. Moreover, FSTL1was found to inhibit insulin signaling and translocation of GLUT4inadipocytes.Conclusion: FSTL1is a novel preadipokine that is closely associated withobesity. It also possesses potent inflammatory activities, with the ability toactivate inflammatory pathways and induce cytokine expression in bothadipocytes and macrophages. Furthermore, FSTL1can impair insulinsensitivity in adipocytes. Thus, FSTL1may be a potential mediator linkingobesity to chronic inflammation and insulin resistance.3. The Anti-inflammatory Actions of GLP-1Objective: to determined the anti-inflammatory actions of GLP-1Methods: the effects of GLP-1on the expression of inflammatory mediatorsand activation of inflammatory pathways in3T3-L1preadipocytes wereevaluated by quantitive PCR and Western blot analysis, before and afterstimulation with conditioned medium from macrophages. Moreover, the effects of GLP-1on the migration of macrophages induced by preadipocyte-conditioned medium were determined by transwell migration assay.Results: GLP-1inhibited the expression of inflammatory mediators in3T3-L1preadipocytes before and after stimulation with conditioned mediumfrom macrophages. Also, GLP-1suppressed the activation of the NFκBpathway. Moreover, the chemoattractant activities ofpreadipocyte-conditioned medium towards macrophages were markedlydecreased by GLP-1.Conclusion: GLP-1can inhibit the inflammatory mediator expression inpreadipocytes and decrease the chemoattractant activities of preadipocytestowards macrophages. Thus, GLP-1possesses potent anti-inflammatoryactivities.