| dc.description.abstract | Obesity 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 |
