Valproic Acid Inhibits Leptin Secretion and Reduces Leptin Messenger Ribonucleic Acid Levels in Adipocytes

Lagace, Diane C.; McLeod, Roger S.; Nachtigal, Mark W.

doi:10.1210/en.2004-0877

Cited by 47 publications

(49 citation statements)

References 86 publications

(74 reference statements)

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“…Mouse Adipocyte Cell Culture-3T3-L1 preadipocytes were obtained from the American Tissue Culture Collection (Manassas, VA) and grown according to standard protocols (36). Confluent preadipocytes were differentiated in adipocyte media (DMEM, 10% FBS, 850 nM insulin, and 0.1% penicillin/ streptomycin) supplemented with 250 nM dexamethasone and 100 M isobutylmethylxanthine (IBMX) for 3 days.…”

Section: Methodsmentioning

confidence: 99%

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Chemerin, a Novel Adipokine That Regulates Adipogenesis and Adipocyte Metabolism

Goralski

McCarthy

Hanniman

et al. 2007

Journal of Biological Chemistry

730

776

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Obesity is an alarming primary health problem and is an independent risk factor for type II diabetes, cardiovascular diseases, and hypertension. Although the pathologic mechanisms linking obesity with these co-morbidities are most likely multifactorial, increasing evidence indicates that altered secretion of adipose-derived signaling molecules (adipokines; e.g. adiponectin, leptin, and tumor necrosis factor ␣) and local inflammatory responses are contributing factors. Chemerin (RARRES2 or TIG2) is a recently discovered chemoattractant protein that serves as a ligand for the G protein-coupled receptor CMKLR1 (ChemR23 or DEZ) and has a role in adaptive and innate immunity. Here we show an unexpected, high level expression of chemerin and its cognate receptor CMKLR1 in mouse and human adipocytes. Cultured 3T3-L1 adipocytes secrete chemerin protein, which triggers CMKLR1 signaling in adipocytes and other cell types and stimulates chemotaxis of CMKLR1-expressing cells. Adenoviral small hairpin RNA targeted knockdown of chemerin or CMKLR1 expression impairs differentiation of 3T3-L1 cells into adipocytes, reduces the expression of adipocyte genes involved in glucose and lipid homeostasis, and alters metabolic functions in mature adipocytes. We conclude that chemerin is a novel adipose-derived signaling molecule that regulates adipogenesis and adipocyte metabolism.

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Section: Methodsmentioning

confidence: 99%

“…Between 2 and 30 min thereafter, media were removed, and 100 l of 1ϫ Laemmli buffer was added to stop the reaction and lyse the adipocytes. Oil Red O staining of adipocytes and quantification of extracted dye were carried out as described previously (36).…”

Section: Methodsmentioning

confidence: 99%

Chemerin, a Novel Adipokine That Regulates Adipogenesis and Adipocyte Metabolism

Goralski

McCarthy

Hanniman

et al. 2007

Journal of Biological Chemistry

730

776

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“…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]. Elucidating the mechanisms of VPA-induced weight gain could help develop more effective antiepileptic therapies, but might also provide insight into the development of metabolic imbalances and the etiology of obesity.…”

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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“…19 Conversely, adipogenic agents like the thiazolinediones and valproic acid reduce leptin secretion. [20][21][22] Furthermore, adipocyte-selective reduction of leptin receptors leads to adiposity in mice, despite a normal level of hypothalamic leptin receptors and normal food intake. 16 These findings suggest adipogenic role of hypoleptinemia.…”

mentioning

confidence: 99%

Adipogenic human adenovirus-36 reduces leptin expression and secretion and increases glucose uptake by fat cells

et al. 2006

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Objective: Human adenovirus Ad-36 causes adiposity in animal models and enhances differentiation and lipid accumulation in human and 3T3-L1 preadipocytes, which may, in part, explain the adipogenic effect of Ad-36. We determined the consequences of Ad-36 infection on leptin and glucose metabolism in fat cells. Design: 3T3-L1 preadipocytes were used to determine the effect of infection by human adenoviruses Ad-36, Ad-2, Ad-9 and Ad-37 on leptin secretion and lipid accumulation. Rat primary adipocytes were used to determine the effect of Ad-36 infection on leptin secretion and glucose uptake in vitro. Furthermore, the effect of Ad-36 on expressions of leptin and selected genes of de novo lipogenesis pathway of visceral adipose tissue were compared ex vivo, between Ad-36 infected and uninfected control rats. Results: Ad-36 suppressed the expression of leptin mRNA in 3T3-L1 cells by approximately 58 and 52% on days 3 and 5 postinfection, respectively. Leptin release normalized to cellular lipid content was 51% lower (Po0.002) in the Ad-36 infected 3T3-L1 cells. Lipid accumulation was significantly greater and leptin secretion was lower for the 3T3-L1 cells infected with other human adenoviruses Ad-9, Ad-36, or Ad-37. Whereas, human adenovirus Ad-2 did not influence cellular lipid accumulation or the leptin release. In rat primary adipocytes, Ad-36 reduced leptin release by about 40% in presence of 0.48 (Po0.01) or 1.6 nM insulin (Po0.05) and increased glucose uptake by 93% (Po0.001) or 18% (Po0.05) in presence of 0 or 0.48 nM insulin, respectively. Next, the adipose tissue of Ad-36 infected rats showed two to fivefold lower leptin mRNA expression, and 1.6-to 21-fold greater expressions for acetyl Co-A carboxylase-1 and 1.2-to 6.3-fold greater expressions for fatty acid synthase, key genes of de novo lipogenesis, compared to the uninfected weight and adiposity matched controls. Conclusion: The in vitro and ex vivo studies show that Ad-36 modulates adipocyte differentiation, leptin production and glucose metabolism. Whether such a modulation contributes to enhanced adipogenesis and consequent adiposity in Ad-36 infected animals or humans needs to be determined.

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Valproic Acid Inhibits Leptin Secretion and Reduces Leptin Messenger Ribonucleic Acid Levels in Adipocytes

Cited by 47 publications

References 86 publications

Chemerin, a Novel Adipokine That Regulates Adipogenesis and Adipocyte Metabolism

Chemerin, a Novel Adipokine That Regulates Adipogenesis and Adipocyte Metabolism

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

Adipogenic human adenovirus-36 reduces leptin expression and secretion and increases glucose uptake by fat cells

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