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A PDE1 Inhibitor Reduces Adipogenesis in Mice Via Regulation

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A PDE1 Inhibitor Reduces Adipogenesis in Mice Via Regulation Kim et al. Experimental & Molecular Medicine (2019) 51:5 https://doi.org/10.1038/s12276-018-0198-7 Experimental & Molecular Medicine ARTICLE Open Access A PDE1 inhibitor reduces adipogenesis in mice via regulation of lipolysis and adipogenic cell signaling Nam-Jun Kim1,2,Jung-HwanBaek1,2,JinAhLee1,2,HyeNaKim1,3, Jun-Kyu Song1,2 and Kyung-Hee Chun1,2 Abstract Vinpocetine, a phosphodiesterase (PDE) type-1 inhibitor, increases cAMP and cGMP levels and is currently used for the management of cerebrovascular disorders, such as stroke, cerebral hemorrhage, and cognitive dysfunctions. In this study, we first determined that vinpocetine effectively suppressed adipogenesis and lipid accumulation. However, we questioned which molecular mechanism is involved because the role of PDE in adipogenesis is still controversial. Vinpocetine decreased adipogenic cell signaling, including the phosphorylation of ERK, AKT, JAK2, and STAT3, and adipokine secretion, including IL-6, IL-10, and IFN-α. Interestingly, vinpocetine increased the phosphorylation of HSL, suggesting the induction of the lipolysis pathway. Moreover, vinpocetine increased UCP1 expression via increasing cAMP and PKA phosphorylation. The administration of vinpocetine with a normal-chow diet (NFD) or a high-fat diet (HFD) in mice attenuated body weight gain in mice fed both the NFD and HFD. These effects were larger in the HFD- fed mice, without a difference in food intake. Vinpocetine drastically decreased fat weight and adipocyte cell sizes in gonadal and inguinal white adipose tissues and in the liver in both diet groups. Serum triacylglycerol levels and fasting blood glucose levels were reduced by vinpocetine treatment. This study suggested that vinpocetine prevents adipocyte differentiation through the inhibition of adipogenesis-associated cell signaling in the early stages of 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; adipogenesis. Moreover, upregulating cAMP levels leads to an increase in lipolysis and UCP1 expression and then inhibits lipid accumulation. Therefore, we suggest that vinpocetine could be an effective agent for treating obesity, as well as improving cognition and cardiovascular function in older individuals. Introduction adipocyte hypertrophy (increased cell size), adipocyte The immoderate accumulation of fat tissue, the result of hyperplasia (increased adipocyte number) mainly occurs an imbalance between energy intake and expenditure, in children and unhealthy obese individuals4. Therefore, causes obesity1. Obesity is a major worldwide issue that developing an effective way to ameliorate adiposity is an increases the incidence of type 2 diabetes mellitus, car- important goal in metabolic disease research. There have diovascular diseases, hepatosteatosis, hyperlipidemia, and been efforts by many researchers to find anti-obesity other chronic diseases2,3 Obesity is the result of a change therapeutic targets. However, most of the anti-obesity in both adipocyte number and the size of individual fat agents reported to date are chemical compounds with side cells. While adult-onset obesity is generally due to effects, such as diarrhea, vomiting, nausea, and insomnia5. To overcome these side effects, many scientists have sought to identify natural compounds that have anti- Correspondence: Kyung-Hee Chun ([email protected]) 6,7 1Department of Biochemistry and Molecular Biology, Yonsei University College adipogenic effects . In this study, we used a screening of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea approach to identify natural compounds with anti-obesity 2 Brain Korea 21 PLUS Project for Medical Science, Yonsei University, 50 Yonsei- effects. First, we purchased a library of 502 natural com- ro, Seodaemun-gu, Seoul, Republic of Korea Full list of author information is available at the end of the article. pounds and administered them to cultured pre-adipocytes These authors contributed equally: Nam-Jun Kim, Jung-Hwan Baek © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Korean Society for Biochemistry and Molecular Biology Kim et al. Experimental & Molecular Medicine (2019) 51:5 Page 2 of 15 at 25 μg/ml to study their effects on adipocyte differ- MA). 3T3-L1 cells were cultured in Dulbecco’s modified entiation, especially on the second day of treatment. We Eagle’s medium (DMEM) containing 10% calf serum until selected anti-obesity compounds through Oil Red O confluence. Then, differentiation was induced in DMEM (ORO) staining. Among the screened compounds, we containing 10% FBS, insulin (1 μg/ml), iso- excluded compounds known to act as tumor inducers, butylmethylxanthine (520 μM), and dexamethasone anti-cancer drugs, and blood pressure reducers as well as (1 μM) (MDI). After 2 days, the medium was replaced compounds with cytotoxicity. Finally, we identified that with DMEM supplemented with 10% FBS and insulin vinpocetine has anti-obesity effects based on the results of (1 μg/ml). Then, DMEM containing 10% FBS without ORO staining. insulin was replaced every 2 days until day 6. Vinpocetine is a semisynthetic derivative of vincamine, an alkaloid first extracted from the periwinkle plant dur- Cell viability assay ing the late 1960s8,9. It has been demonstrated that vin- 3T3-L1 cells were plated in 12-well plates and incubated pocetine is a phosphodiesterase type-1 (PDE1) inhibitor until confluence. Then, confluent 3T3-L1 cells were that increases intracellular cGMP and cAMP concentra- treated with vinpocetine for the indicated time. Cell via- tions, thereby activating protein kinase A and protein bility was measured using EZ-Cytox (Daeil Lab Services, – kinase G (PKG), respectively10 12. Vinpocetine relaxes Wonju, Korea) according to the manufacturer’s cerebral smooth muscle cells and ameliorates cerebral protocol19,20. blood flow13,14. Considering its favorable effects of vaso- dilation and neuro-protection, vinpocetine has been Western blot assay widely used for decades in the treatment of cere- Cell lysate extractions were prepared with radio- brovascular diseases. Vinpocetine ameliorates neuroplas- immunoprecipitation assay buffer (1% Triton X-100, 1% + ticity via an increase in Ca2 and cAMP/cGMP levels, sodium deoxycholate, 0.1% sodium dodecyl sulfate, inducing a cascade that causes the phosphorylation and 150 mM NaCl, 50 mM Tris–HCl, pH 7.5, and 2 mM – activation of cAMP responsive element binding protein EDTA, pH 8.0) as described previously21 23. Antibodies (CREB) and serum response factor (SRF). Activation of against C/EBPα, C/EBPβ, PPARγ, A-FABP, FASN, AKT, CREB or SRFs promotes the expression of neuroplasticity- p-AKT, AMPKα1/2, p-AMPKα1/2, JAK2, p-JAK2, HSL, associated genes15. Recently, vinpocetine was reported to and PGC1α were purchased from Santa Cruz Bio- inhibit the proliferation of vascular smooth muscle cells technology (Dallas, TX). Antibodies against ERK, p-ERK, and breast cancer cells16. Furthermore, vinpocetine was STAT3, p-STAT3, p-HSL, PKA, p-PKA, and UCP1 were identified as a potent anti-inflammatory agent. It prohibits obtained from Cell Signaling Technology (Danvers, MA). NFκB transcription after stimulation of TNFα by blocking The normalization control was anti-β-actin (Santa Cruz the IκB kinase complex (IKK)17. However, the anti-obesity Biotechnology). effects of vinpocetine have not previously been investigated. cAMP direct immunoassay In this study, we demonstrated the molecular mechan- Differentiated 3T3L1 cells were incubated in 0.1 M HCl isms by which vinpocetine affects adipocyte differentia- for 10 min at room temperature to detach cells from the tion and lipid accumulation. We also administered plate. The cAMP level was measured from supernatants vinpocetine to mice on a high-fat diet (HFD) and deter- using an ELISA kit in accordance with the manufacturer’s mined its anti-obesity effect in vivo. Taken together, we instructions (Enzo Life Science, Farmingdale, NY). suggest that vinpocetine could be a potent agent for obesity treatment. Oxygen consumption rate (OCR) assay 3T3-L1 cells were seeded in an XF24 microplate and Materials and methods treated with vinpocetine at 2 days after MDI treatment. Chemicals After 3 days, the XF24 microplate was incubated in a non- An FDA-approved natural product chemical library was CO2 incubator for 1 h, and respiration was measured purchased from Enzo Life Sciences (Farmingdale, NY). under basal conditions, followed by the addition of 2.6 μM Vinpocetine, isobutylmethylxanthine, dexamethasone, oligomycin, 0.5 μM FCCP, and 1 μM rotenone/antimycin insulin, and ORO powder were purchased from Sigma A. OCRs were measured using an XF24 analyzer Chemicals (St. Louis, MO). (Seashore Bioscience). Cell culture ORO staining 3T3-L1 cells were maintained
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