Valproate, weight gain and carbohydrate craving: A gender study

El-Khatib, Firas; Rauchenzauner, Markus; Lechleitner, Monika; Hoppichler, Fritz; Naser, Anis; Waldmann, Markus; Trinka, Eugen; Unterberger, Iris; Bauer, Gerhard; Luef, Gerhard

doi:10.1016/j.seizure.2006.12.009

Cited by 83 publications

(71 citation statements)

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“…One of the most common, and unwanted, side effects of VPA therapy is the significant weight gain that predominantly occurs during the first 3–6 months of treatment [1]. In our experiments, VPA failed to have any effect on body weight or gene expression in male CD-1 mice, although a modest increase in rstn expression was detected in fat 24 h after VPA was injected.…”

Section: Discussionmentioning

confidence: 54%

“…We employed 2 doses (100 mg/kg, 24 h; 200 mg/kg, 72 h) that are clearly much higher than those used clinically (20–30 mg/kg) in humans [1, 8]. However, the use of such high doses in mice has been justified, since it reproduced the plasma concentrations that are normally measured in patients treated with therapeutic doses of VPA [8, 38, 39].…”

Section: Discussionmentioning

confidence: 99%

“…Valproic acid (VPA), an antiepileptic drug, is used as a mood stabilizer and anticonvulsant, but also induces significant weight gain by unresolved mechanisms [1,2,3]. This deleterious effect of VPA therapy is particularly concerning, since it reduces patient compliance and increases the risk of infertility, development of diabetes or cardiovascular disease [1, 2, 4, 5].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…This deleterious effect of VPA therapy is particularly concerning, since it reduces patient compliance and increases the risk of infertility, development of diabetes or cardiovascular disease [1, 2, 4, 5]. Recently, VPA was proposed to induce a state of leptin resistance, much like obesity, leading to increases in appetite and body weight [1, 5]. At the molecular level, VPA was shown to inhibit histone deacetylase (HDAC) activity [6, 7], but its metabolic actions could be due to its inhibitory effects on the adipogenic transcription factor CCAAT enhancer binding protein α (CEBPα) [8, 9].…”

Section: Introductionmentioning

confidence: 99%

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

Brown¹,

Imran²,

Ur³

et al. 2008

Neuroendocrinology

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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.

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Section: Discussionmentioning

confidence: 54%