Rosiglitazone, a PPAR γ Agonist Promotes Neuronal Survival by Up-Regulating Neuroprotective Protein Carboxypeptidase E Expression

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 338-365-Metabolic & Stress Receptors in Energy Homeostasis
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-358
Erwan Thouennon*1, Yong Cheng1, Beata Lecka-Czernik2 and Yoke Peng Loh1
1National Institutes of Health, Bethesda, MD, 2Univ of Toledo Coll of Med, Toledo, OH
Rosiglitazone (Avandia - RGZ), belongs to the thiazolidinediones (TZDs) class of drugs that are peroxisome proliferator-activated receptor-γ (PPARG) agonists. TZDs activate PPARG to reduce the systemic insulin resistance in peripheral tissues and lower plasma glucose levels, and have been used to treat type 2 diabetes patients. Subsequently, activation of PPARG was found to be involved in a large number of pathophysiological conditions including atherosclerosis, inflammation, obesity, cancer. Interestingly, RGZ has been reported to exert a neuroprotective effect on hippocampal neurons through a Bcl-2 dependant pathway. We have recently shown that Carboxypeptidase-E (CPE), a prohormone processing enzyme is a new neuroprotective trophic factor. In hippocampal neurons, secreted or exogenous recombinant CPE was able to exert a positive effect on cell survival by up-regulating the expression of the anti-apoptotic protein, Bcl-2. Here we investigated whether RGZ could mediate its neuroprotective effects by modulating the expression of CPE. We found that CPE mRNA/protein levels were significantly up-regulated in the hippocampus of RGZ-fed mice and in rat hippocampal neurons treated with RGZ. Bioinformatic analysis demonstrated the presence of evolutionary conserved putative PPARG-binding sites in the CPE promoter. To investigate if transcription of CPE could be directly modulated by RGZ at the promoter level, we designed a luciferase construct containing the CPE promoter and transfected it into embryonic (E13.5) primary cortical neurons. We found that in those cells, RGZ treatment was able to significantly increase the luciferase activity, in comparison with neurons transfected with a construct in which PPARG-binding sites were removed. This indicated that regulation of CPE expression by RGZ occurs through direct binding of PPARG to the CPE promoter and provides a mechanism underlying the effects of RGZ in neuronal cell survival.

Nothing to Disclose: ET, YC, BL, YPL

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