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dc.contributor.authorPassaretti, Federica
dc.date.accessioned2014-07-08T13:22:46Z
dc.date.available2014-07-08T13:22:46Z
dc.date.issued2014-03-21
dc.identifier.urihttp://hdl.handle.net/10556/1468
dc.identifier.urihttp://dx.doi.org/10.14273/unisa-311
dc.description2012 - 2013en_US
dc.description.abstractObesity is a chronic disorder characterized by a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time. In addition, obesity is often accompanied by elevations in tissue and circulating FFA concentrations. Systemic levels of FFAs can induce inflammatory cascades in adipocytes and macrophages through TLR4-dependent effect. Signaling through TLR4 activates a broad range of intracellular cascades that include stimulation of IKK-β, NF-kB, JNK and AP1. Indeed, in addition to store excess calories in the form of lipid, adipose tissue produces classical cytokines and chemokines such as MCP-1, IL-8 and CCL5. CCL5, as other chemokines, participates in mediating leukocyte infiltration of adipose tissue. Moreover circulating CCL5 concentrations are elevated in obesity, impaired glucose tolerance (IGT) and type 2 diabetes. In this study I have investigated the molecular mechanisms involved in the metabolic control of CCL5 expression in adipocytes. Cytokine/growth factor screening of conditioned media from 3T3-L1 preadipocytes and adipocytes revealed that adipocytes secreted higher amount of CCL5 compared to their undifferentiated precursors. Higher concentrations of glucose and fatty acids (oleate and palmitate) increased CCL5 secretion by 3T3-L1 adipocytes. Moreover, both oleate and palmitate enhanced CCL5 mRNA levels and induced an activation of JNK, NF-kB, MAPK and PI3K/AKT pathways. In cells treated with JSH23, a NF-kB inhibitor, the effect of FFAs on CCL5 mRNA levels was reduced thus indicating a direct involvement of NF-kB. Treatment of the cells with SP600125, a JNK inhibitor, also significantly reduced the stimulatory effect of oleate and palmitate on CCL5 mRNA and interestingly prevented FFA-induced NF-kB binding to CCL5 promoter. I have also obtained evidence that insulin exerted an inhibitory effect on CCL5 mRNA and counteracted fatty acid-induced stimulation. Both PD98059 and LY294002, inhibitors of MAPK and PI3K, respectively, increased CCL5 expression levels reverted anti-inflammatory effect of insulin in presence of fatty acids. Consistently, insulin exposure reduced NF-kB recruitment onto CCL5 promoter, and almost completely prevented fatty acid effect. In conclusion, oleate and palmitate induce CCL5 mRNA, possibly via JNK and NF-kB pathways. Fatty acid effect on CCL5 is largely prevented by insulin and may involve PI3K/AKT and MAPK. [edited by author]en_US
dc.language.isoenen_US
dc.publisherUniversita degli studi di Salernoen_US
dc.subjectTessuto adiposoen_US
dc.subjectAcidi grassien_US
dc.subjectChemokinesen_US
dc.titleMolecular pathways involved in metabolic control of CCL5 in adipocytesen_US
dc.typeDoctoral Thesisen_US
dc.subject.miurMED/05 PATOLOGIA CLINICAen_US
dc.contributor.coordinatoreBifulco, Maurizioen_US
dc.description.cicloXII n.s.en_US
dc.contributor.tutorFormisano, Pietroen_US
dc.identifier.DipartimentoFarmaciaen_US
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