Regulation of PPARgamma Activity by mTOR in Adipogenesis
Kim, Jae Eun
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Permalink
https://hdl.handle.net/2142/86672
Description
Title
Regulation of PPARgamma Activity by mTOR in Adipogenesis
Author(s)
Kim, Jae Eun
Issue Date
2004
Doctoral Committee Chair(s)
Chen, Jie
Department of Study
Microbiology
Discipline
Microbiology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Cell
Language
eng
Abstract
This study reveals a novel regulatory mechanism of mammalian target of rapamycin mTOR signaling, which involves cytoplasmic-nuclear shuttling of mTOR. As direct evidence, data show that leptomycin B (LMB), a specific inhibitor of nuclear export receptor Crm1 confers the accumulation of nuclear mTOR. Further investigation by altering mTOR's nuclear shuttling activity with exogenous nuclear import and export signals has proved a direct link between nuclear shuttling of mTOR and S6K1 activation/4E-BP1 phosphorylation. Furthermore, it was found that nuclear shuttling of mTOR regulates mitogen-stimulated rapamycin-sensitive translation initiation. These findings uncover a function for the nucleus in the direct regulation of the protein synthesis machinery via extracellular signals. Next, tissue-specific roles of mTOR were investigated by using an adipogenesis model system. Herein, I show that mTOR plays a critical role in adipocyte differentiation and the maintenance of mature adipocytes, and that its kinase activity is required. Rapamycin specifically disrupted the positive transcriptional feedback loop between C/EBPalpha and PPARgamma. The PPARgamma activity toward its target genes was specifically inhibited by rapamycin upon insulin stimulation. I demonstrate that PPARgamma activity is dependent on amino acid sufficiency, revealing a molecular link between nutrient status and adipogenesis. I propose a model in which the mTOR pathway and the PI3K/Akt pathway act in parallel to regulate PPARgamma activation during adipogenesis, by mediating nutrient availability and insulin signals, respectively. A thiazolidinediones drug troglitazone was found to reverse the inhibitory effects of both rapamycin and amino acid deprivation, implicating therapeutic value of these drugs to counter side effects of rapamycin as an immunosuppressant. A potential role of mTOR in IL-6 stimulated STAT3 pathway was also investigated and possible link to the regulation of insulin sensitivity will be discussed. We found that rapamycin changes the time course of IL-6 stimulated STAT3 phosphorylation in hepatocytes, which may cause changes in the expression profiles of downstream targets. In the case of adipocytes, no significant change was observed in STAT3 phosphorylation with IL-6 stimulation. Thus, IL-6 appears to exert differential autocrine/paracrine effects on different tissues.
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