Cilostazol increases 3T3-L1 preadipocyte differentiation with improved glucose uptake associated with activation of peroxisome proliferator-activated receptor-γ transcription

Park, So Youn; Lee, Jeong Hyun; Kim, Ki Young; Kim, Eun Kyoung; Yun, Sung Ji; Kim, Chi Dae; Lee, Won Suk; Hong, Ki Whan

doi:10.1016/j.atherosclerosis.2008.02.006

Cited by 28 publications

(19 citation statements)

References 29 publications

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“…It also decreased plasma insulin and resistin levels. These results are consistent with previous in vitro findings (Park et al, 2008), in which the resistin-induced decreased GLUT4 expression was reversed in accordance with recovery of glucose uptake after treatment with cilostazol. Again, this was similar to rosiglitazone.…”

Section: Discussionsupporting

confidence: 82%

“…Cilostazol down-regulated resistin expression and up-regulated adiponectin expression in 3T3-L1 adipocytes in conjunction with increased GLUT4 expression/translocation in adipocytes and glucose uptake in L6 myotube cell lines. These effects are similar to rosiglitazone, a PPAR␥ agonist (Park et al, 2008). Given that cilostazol up-regulates GLUT4 expression/translocation, along with increased expression of adiponectin via increased PPAR␥ transcription in 3T3-L1 fibroblast cells, it is likely that cilostazol may improve insulin sensitivity in type 2 diabetic patients.…”

mentioning

confidence: 57%

“…In previous experiments with COS-7 cells and human umbilical vein endothelial cells (Park et al, 2008), we observed that cilostazol increased PPAR␥ transcriptional activity, as did rosiglitazone. These increased activities are antagonized by GW9662 (Leesnitzer et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Cilostazol Ameliorates Metabolic Abnormalities with Suppression of Proinflammatory Markers in a db/db Mouse Model of Type 2 Diabetes via Activation of Peroxisome Proliferator-Activated Receptor γ Transcription

Park¹,

Shin²,

Lee³

et al. 2009

J Pharmacol Exp Ther

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In a previous study, cilostazol promoted differentiation of 3T3-L1 fibroblasts into adipocytes and improved insulin sensitivity by stimulating peroxisome proliferator-activated receptor (PPAR) ␥ transcription. This study evaluated the in vivo efficacy of cilostazol to protect a db/db mouse model of type 2 diabetes against altered metabolic abnormalities and proinflammatory markers via activation of PPAR␥ transcription. Eight-week-old db/db mice were treated with cilostazol or rosiglitazone for 12 days. Cilostazol significantly decreased plasma glucose and triglyceride levels, as did rosiglitazone, a PPAR␥ agonist. Elevated plasma insulin and resistin levels were significantly decreased by cilostazol, and decreased adiponectin mRNA expression was elevated along with increased plasma adiponectin. Cilostazol significantly increased both adipocyte fatty acid binding protein and fatty acid transport protein-1 mRNA expressions with increased glucose transport 4 in the adipose tissue. Cilostazol and rosiglitazone significantly suppressed proinflammatory markers (superoxide, tumor necrosis factor-␣, and vascular cell adhesion molecule-1) in the carotid artery of db/db mice. In an in vitro study with 3T3-L1 fibroblasts, cilostazol significantly increased PPAR␥ transcription activity, as did rosiglitazone. The transcription activity stimulated by cilostazol was attenuated by KT5720 [(9R,10S,12S)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9, 12-epoxy-1H-diindolo[1,2,3-fg:3Ј,2Ј,1Ј-kl]pyrrolo [3,4-I][1,6]-benzodiazocine-10-carboxylic acid hexyl ester], a cAMPdependent protein kinase inhibitor, and GW9662 (2-chloro-5-nitrobenzanilide), an antagonist of PPAR␥ activity, indicative of implication of the phosphatidylinositol 3-kinase/Akt signal pathway. These results suggest that cilostazol may improve insulin sensitivity along with anti-inflammatory effects in type 2 diabetic patients via activation of both cAMP-dependent protein kinase and PPAR␥ transcription.Insulin resistance is a major contributor to the pathogenesis of type 2 diabetes and plays a key role in associated metabolic abnormalities, such as dyslipidemia and hypertension (Goldstein, 2002). Adipose tissue was recognized recently as a primary site of insulin resistance, rather than skeletal muscle (Hotamisligil, 2000). Arner (2003) emphasized that adipocytokines, such as tumor necrosis factor (TNF)-␣, adiponectin, and resistin, modulate the underlying insulin resistance.Peroxisome proliferator-activated receptor (PPAR) ␥, as a receptor for the thiazolidinediones, plays a key role in adipogenesis (Vidal-Puig et al., 1997). Thiazolidinediones

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Section: Discussionsupporting

confidence: 82%

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confidence: 57%

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Cilostazol Ameliorates Metabolic Abnormalities with Suppression of Proinflammatory Markers in a db/db Mouse Model of Type 2 Diabetes via Activation of Peroxisome Proliferator-Activated Receptor γ Transcription

Park¹,

Shin²,

Lee³

et al. 2009

J Pharmacol Exp Ther

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“…20,21 Cilostazol can also stimulate differentiation of fibroblasts into adipocytes and stimulate PPAR-gamma transcription, which may contribute to the increased serum adiponectin levels. 22 In this study, cilostazol treatment alleviated chronic inflammation (high hs-CRP and low adiponectin) in both groups of DM patients; the increase in adiponectin was more apparent in the PAOD group.…”

Section: Discussionmentioning

confidence: 88%

Effect of Cilostazol Treatment on Adiponectin and Soluble CD40 Ligand Levels in Diabetic Patients With Peripheral Arterial Occlusion Disease

Hsieh

Wang

2009

Circ J

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Circ J 2009; 73: 948 -954 eripheral arterial occlusion disease (PAOD) is a common manifestation of atherosclerosis in patients with type 2 diabetes mellitus (DM). 1,2 In Taiwan, approximately 33-50% of patients undergoing lower extremity amputation have DM, and more than 50% of them have PAOD. 3,4 The risk factors associated with PAOD are similar to those for coronary artery disease and cerebrovascular disease.It has been proved that atherosclerosis-related macroangiopathy is a result of chronic inflammation and endothelium dysfunction. Levels of high-sensitivity C-reactive protein (hs-CRP) and adiponectin have been found to be markers of chronic inflammation in many human studies. [5][6][7] Interaction of the multipotent immunomodulator CD40 ligand with its receptor is also as an important contributor to chronic inflammation and endothelium dysfunction. The soluble form of the CD40 ligand (sCD40L), a marker of proinflammatory and platelet activation, is high in the sera of DM patients with coronary artery disease. 8 However, few studies have investigated the relationships between PAOD and adiponectin and sCD40L levels.Cilostazol, a vasodilator and inhibitor of platelet aggregation, has been used in the treatment of chronic PAOD since 1988. Because little is known regarding its effects on PAOD and the aforementioned atherogenic cytokines in DM patients, we performed a randomized, placebo-controlled, single-blinded trial to examine the effect of cilostazol treatment on the serum levels of sCD-40L, adiponectin and hs-CRP in patients with type 2 DM. Methods SubjectsWe enrolled 92 PAOD patients (53 women, 39 men; mean age 63.3±18.8 years) and 100 non-PAOD patients as controls (58 women, 42 men; mean age 63.0±14.7 years) at our outpatient clinic from 2006 to 2008. Sex ratio and ranges of age and body mass index (BMI) were considered while selecting the controls. All patients were confirmed to have type 2 DM based on the 2005 American Diabetes Association diagnostic criteria and had received oral antidiabetic drugs (OADs) for more than 6 months. Because some antiplatelet, antihypertension and antihyperlipidemia drugs have an antiinflammatory effect, the dosages of all medications, including OADs, aspirin, antihypertension drugs and antihyperlipidemia drugs, were not changed for 6 months prior to the study or during the study period. We excluded any patient who had received insulin injections for more than 1 month or had been found to have had cardiogenic shock, unstable angina, old stroke, or myocardial infarction during the preceding 6 months, had an ankle systolic blood pressure (SBP) ≥200 mmHg, had been treated with insulin, and had impaired renal function (creatinine level >1.4 mg/dl), cancer, systemic inflammatory disease or (Received September 24, 2008; revised manuscript received November 26, 2008; accepted December 15, 2008; released online March 12, 2009 Effect of Cilostazol Treatment on Adiponectin and Soluble CD40 Ligand Levels in Diabetic Patients With Peripheral Arterial Occlusion DiseaseChing-Jung...

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“…We are aware that the concentrations used in our study for TNFα and isoproterenol -although based on previous studies (Gauthier et al, 2008;Jones et al, 2005;Kim et al, 2005;Park et al, 2008;Haemmerle et al, 2006;Souza et al, 1998) -are too high and thus supra-physiological. However, these two molecules were used as positive controls to compare the effects triggered by FCCP, and the concentrations were selected to maximize expected biological responses while minimizing toxic effects.…”

Section: Gene Expression Analysis During the De-differentiation Of 3tmentioning

confidence: 99%

Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differentiation by a PPARγ-independent mechanism, whereas TNFα-induced de-differentiation is PPARγ dependent

Tejerina

Pauw

Vankoningsloo

et al. 2009

Journal of Cell Science

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Impairment of mitochondrial activity affects lipid-metabolizing tissues and mild mitochondrial uncoupling has been proposed as a possible strategy to fight obesity and associated diseases. In this report, we characterized the 3T3-L1-adipocyte `de-differentiation' induced by carbonyl cyanide (p-trifluoromethoxy)-phenylhydrazone (FCCP), a mitochondrial uncoupler. We found a decrease in triglyceride (TG) content in adipocytes incubated with this molecule. We next analyzed the expression of genes encoding adipogenic markers and effectors and compared the differentially expressed genes in adipocytes treated with FCCP or TNFα (a cytokine known to induce adipocyte de-differentiation). Furthermore, a significant decrease in the transcriptional activity of PPARγ and C/EBPα transcription factors was found in adipocytes with impaired mitochondrial activity. However, although these modifications were also found in TNFα-treated adipocytes, rosiglitazone and 9-cis retinoic acid (PPARγ and RXR ligands) were unable to prevent triglyceride loss in FCCP-treated cells. Metabolic assays also revealed that TG reduction could be mediated by a downregulation of lipid synthesis rather than an upregulation of fatty acid oxidation. Finally, lipolysis stimulated by the uncoupler also seems to contribute to the TG reduction, a process associated with perilipin A downregulation. These results highlight some new mechanisms that might potentially be involved in adipocyte de-differentiation initiated by a mitochondrial uncoupling.

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Cilostazol increases 3T3-L1 preadipocyte differentiation with improved glucose uptake associated with activation of peroxisome proliferator-activated receptor-γ transcription

Cited by 28 publications

References 29 publications

Cilostazol Ameliorates Metabolic Abnormalities with Suppression of Proinflammatory Markers in a db/db Mouse Model of Type 2 Diabetes via Activation of Peroxisome Proliferator-Activated Receptor γ Transcription

Cilostazol Ameliorates Metabolic Abnormalities with Suppression of Proinflammatory Markers in a db/db Mouse Model of Type 2 Diabetes via Activation of Peroxisome Proliferator-Activated Receptor γ Transcription

Effect of Cilostazol Treatment on Adiponectin and Soluble CD40 Ligand Levels in Diabetic Patients With Peripheral Arterial Occlusion Disease

Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differentiation by a PPARγ-independent mechanism, whereas TNFα-induced de-differentiation is PPARγ dependent

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