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Vol. 88, No. 1, 2008
Issue release date: July 2008
Section title: Appetite and Energy Balance
Neuroendocrinology 2008;88:25–34
(DOI:10.1159/000113927)

Valproic Acid and CEBPα-Mediated Regulation of Adipokine Gene Expression in Hypothalamic Neurons and 3T3-L1 Adipocytes

Brown R. · Imran S.A. · Ur E. · Wilkinson M.
Departments of aObstetrics and Gynaecology and bPhysiology and Biophysics and cDivision of Endocrinology and Metabolism, Faculty of Medicine, Dalhousie University, Halifax, N.S., Canada

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Article / Publication Details

First-Page Preview
Abstract of Appetite and Energy Balance

Received: 7/18/2007
Accepted: 12/12/2007
Published online: 1/22/2008

Number of Print Pages: 10
Number of Figures: 5
Number of Tables: 1

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN

Abstract

Background/Aims: Valproic acid (VPA) is the drug of choice for treating epilepsy, but has the unwanted effects of inducing weight gain and increasing the risk of developing insulin resistance. The mechanism through which these side effects occur is unknown. VPA inhibits histone deacetylase (HDAC), but also decreases the transcriptional activity of CCAAT enhancer binding protein α (CEBPα). Given the possible association between VPA, CEBPα and adipokine gene regulation, we hypothesized that they would alter the expression of resistin (rstn), fasting-induced adipose factor (fiaf) and suppressor of cytokine signaling-3 (socs-3), genes implicated in the development of leptin and insulin resistance. Methods: We investigated the effects of VPA (1 mM; 24 or 48 h) on gene expression using real-time RT-PCR in 3 distinct models: N-1 hypothalamic neurons, 3T3-L1 adipocytes and male CD-1 mice. Subsequently, cells were treated with 5 nM of the more specific HDAC inhibitor trichostatin A (TSA). CEBPα expression was also modified in N-1 neurons using either RNA interference (RNAi) or an overexpression vector to evaluate its effects on target gene expression. Results: In N-1 neurons, VPA induced significant increases in CEBPα and socs-3, but inhibited rstn and fiaf gene expression. In contrast, TSA induced rstn and socs-3, but inhibited fiaf. VPA also induced the expression of CEBPαin 3T3-L1 adipocytes, but had no effect on other target genes, and TSA suppressed fiaf and socs-3.Subsequently, CEBPα was overexpressed (24 h) or silenced using RNAi (24 and 48 h) in N-1 neurons. The silencing of CEBPα led to significant decreases in rstn mRNA, but increased fiaf and socs-3 expression, whereas its overexpression had the opposite effect. When male CD-1 mice were treated with either a single (100 mg/kg; 24 h), or multiple (200 mg/kg; 72 h) daily injections of VPA, no changes in body weight or gene expression were detected in either hypothalamic or adipose tissues. Conclusions: In summary, these experiments reveal a potentially important role for CEBPα in the regulation of hypothalamic gene expression in N-1 neurons and suggest that it might modulate central energy metabolism. Although VPA also modified hypothalamic gene expression in vitro, it remains to be determined whether it has similar effects in vivo.


Article / Publication Details

First-Page Preview
Abstract of Appetite and Energy Balance

Received: 7/18/2007
Accepted: 12/12/2007
Published online: 1/22/2008

Number of Print Pages: 10
Number of Figures: 5
Number of Tables: 1

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: http://www.karger.com/NEN


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Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
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