Leptin, ghrelin, and adiponectin in epileptic patients treated with valproic acid

Greco, Rita; Latini, Giuseppe; Chiarelli, Francesco; Iannetti, P.; Verrotti, Alberto

doi:10.1212/01.wnl.0000187074.27586.d1

Cited by 93 publications

(71 citation statements)

References 9 publications

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“…Recently, we demonstrated that adiponectin levels were significantly lower in obese epileptic patients compared with those who did not gain weight, suggesting that patients who showed VPA-induced obesity had similar changes in adiponectin and ghrelin observed in essential obesity [52]. …”

Section: Possible Mechanisms Underlying Vpa-induced Weight Gainmentioning

confidence: 99%

Valproate-Induced Insulin Resistance and Obesity in Children

et al. 2009

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Background: Valproic acid (VPA), a widely used antiepileptic drug, has broad-spectrum activity against both generalized and partial epilepsy. Among the side effects of VPA, weight gain is frequently reported, although the real incidence and magnitude of this problem is unknown. Its pathogenesis is most likely multifactorial, and is controversial. Methods: In order to evaluate the role of hyperinsulinemia and related hormonal abnormalities in VPA-induced obesity, data from the existing literature have been analyzed and discussed critically. Results: Patients suffering from weight gain show various metabolic and endocrinologic abnormalities. The most frequent are hyperinsulinemia and insulin resistance, hyperleptinemia and leptin resistance, and an increase in the availability of long-chain free fatty acids. Significant weight gain is associated with increased levels of insulin and leptin, suggesting a close relationship between obesity-induced hyperinsulinemia and hyperleptinemia. VPA can directly stimulate pancreatic β-cells and indirectly enhance insulin resistance by suppressing insulin-mediated peripheral glucose uptake. Leptin activation seems to be similar in obese VPA-treated subjects to that seen in otherwise obese subjects. Conclusions: The mechanisms of hyperinsulinemia in VPA-induced weight gain remain unclear, although it is likely that obesity is the cause of hyperinsulinemia and all related metabolic changes. However, this heterogeneous metabolic disorder requires further research.

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Section: Possible Mechanisms Underlying Vpa-induced Weight Gainmentioning

confidence: 99%

Valproate-Induced Insulin Resistance and Obesity in Children

et al. 2009

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“…Recently ghrelin has been investigated with respect to its potential role in epilepsy. Data from human studies in this area are conflicting, with some studies concluding either increased [15,16] or decreased [17][18][19][20][21][22] plasma levels of ghrelin in epileptic patients. Rodent studies are more consistent, with the majority of studies indicating that ghrelin shows an anticonvulsant action in different models [10,[23][24][25], but its mechanism of action is unknown.…”

Section: Introductionmentioning

confidence: 99%

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

et al. 2012

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Ghrelin is a pleiotropic neuropeptide that has been recently implicated in epilepsy. Animal studies performed to date indicate that ghrelin has anticonvulsant properties; however, its mechanism of anticonvulsant action is unknown. Here we show that the anticonvulsant effects of ghrelin are mediated via the growth hormone secretagogue receptor (GHSR). To our surprise, however, we found that the GHSR knockout mice had a higher seizure threshold than their wild-type littermates when treated with pilocarpine. Using both in vivo and in vitro models, we further discovered that inverse agonism and desensitization/internalization of the GHSR attenuate limbic seizures in rats and epileptiform activity in hippocampal slices. This constitutes a novel mechanism of anticonvulsant action, whereby an endogenous agonist reduces the activity of a constitutively active receptor.

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“…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%

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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Leptin, ghrelin, and adiponectin in epileptic patients treated with valproic acid

Cited by 93 publications

References 9 publications

Valproate-Induced Insulin Resistance and Obesity in Children

Valproate-Induced Insulin Resistance and Obesity in Children

Inactivation of the Constitutively Active Ghrelin Receptor Attenuates Limbic Seizure Activity in Rodents

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

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