Effect of Metformin and Simvastatin in Inhibiting Proadipogenic Transcription Factors

Overview

Journal Curr Issues Mol Biol

Publisher MDPI

Specialty Molecular Biology

Date 2021 Dec 23

PMID 34940118

Citations 1

Authors

Jelena Jakab

Milorad Zjalic

Stefica Miksic

Ivan Tusek

Vesna Cosic

Nikola Volaric

Dario Nakic

Aleksandar Vcev

Blazenka Miskic

Affiliations

Soon will be listed here.

Abstract

Obesity is a multifactorial chronic disease characterized by the excessive accumulation of fat in adipose tissue driven by hypertrophy and hyperplasia of adipocytes through adipogenesis. Adipogenesis plays a key role in the development of obesity and related metabolic disorders, which makes it potential target for the therapeutic approach to obesity. An increasing number of studies confirm the pleiotropic action of the combined treatment with metformin and statins, suggesting their anti-hypertensive, anti-inflammatory, and anti-adipogenic effect. The aim of this study was to analyze the effect of different doses of metformin (MET) and simvastatin (SIM) on the expression of key transcription factors of adipogenesis. Mouse 3T3-L1 preadipocytes were induced to differentiation in adipogenic medium with sustained MET and SIM treatment to assess the effect on adipogenesis. Nine days after initiating adipogenesis, the cells were prepared for further experiments, including Oil Red O staining, RT-PCR, Western blotting, and immunocytochemistry. Treating the cells with the combination of MET and SIM slightly reduced the intensity of Oil Red O staining compared with the control group, and down-regulated mRNA and protein expression of PPARγ, C/EBPα, and SREBP-1C. In conclusion, the inhibitory effect of MET and SIM on adipocyte differentiation, as indicated by decreased lipid accumulation, appears to be mediated through the down-regulation of adipogenic transcription factors, peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer binding pro-tein α (C/EBPα), and sterol regulatory element-binding protein 1 (SREBP-1C).

Citing Articles

Regulatory Effects of Metformin, an Antidiabetic Biguanide Drug, on the Metabolism of Primary Rat Adipocytes.

Szkudelski T, Konieczna K, Szkudelska K Molecules. 2022; 27(16).

PMID: 36014488 PMC: 9415039. DOI: 10.3390/molecules27165250.

References

Dias S, Paredes S, Ribeiro L . Drugs Involved in Dyslipidemia and Obesity Treatment: Focus on Adipose Tissue. Int J Endocrinol. 2018; 2018:2637418. PMC: 5822899. DOI: 10.1155/2018/2637418. View

Bielczyk-Maczynska E . White Adipocyte Plasticity in Physiology and Disease. Cells. 2019; 8(12). PMC: 6953026. DOI: 10.3390/cells8121507. View

Kim E, Lee S, Jhun J, Byun J, Jeong J, Lee S . Metformin Prevents Fatty Liver and Improves Balance of White/Brown Adipose in an Obesity Mouse Model by Inducing FGF21. Mediators Inflamm. 2016; 2016:5813030. PMC: 4745345. DOI: 10.1155/2016/5813030. View

Alexandre K, Smit A, Gray I, Crowther N . Metformin inhibits intracellular lipid accumulation in the murine pre-adipocyte cell line, 3T3-L1. Diabetes Obes Metab. 2008; 10(8):688-90. DOI: 10.1111/j.1463-1326.2008.00890.x. View

Jackson R, Griesel B, Gurley J, Szweda L, Olson A . Glucose availability controls adipogenesis in mouse 3T3-L1 adipocytes via up-regulation of nicotinamide metabolism. J Biol Chem. 2017; 292(45):18556-18564. PMC: 5682965. DOI: 10.1074/jbc.M117.791970. View

Zjalic M, Mustapic M, Glumac Z, Proloscic I, Blazetic S, Vukovic A . Construction of AC/DC magnetic syringe device for stimulated drug release, injection and ejection of nanocarriers and testing cytotoxicity . MethodsX. 2021; 8:101312. PMC: 8374294. DOI: 10.1016/j.mex.2021.101312. View

Schmitz G, Drobnik W . Pharmacogenomics and pharmacogenetics of cholesterol-lowering therapy. Clin Chem Lab Med. 2003; 41(4):581-9. DOI: 10.1515/CCLM.2003.088. View

Elfakhani M, Torabi S, Hussein D, Mills N, Verbeck G, Mo H . Mevalonate deprivation mediates the impact of lovastatin on the differentiation of murine 3T3-F442A preadipocytes. Exp Biol Med (Maywood). 2014; 239(3):293-301. DOI: 10.1177/1535370213517614. View

Ahmad B, Serpell C, Fong I, Wong E . Molecular Mechanisms of Adipogenesis: The Anti-adipogenic Role of AMP-Activated Protein Kinase. Front Mol Biosci. 2020; 7:76. PMC: 7226927. DOI: 10.3389/fmolb.2020.00076. View

10.

Salvatore T, Pafundi P, Morgillo F, Di Liello R, Galiero R, Nevola R . Metformin: An old drug against old age and associated morbidities. Diabetes Res Clin Pract. 2020; 160:108025. DOI: 10.1016/j.diabres.2020.108025. View

11.

Chen H, Lin M, Muo C, Yeh S, Sung F, Kao C . Combination Therapy of Metformin and Statin May Decrease Hepatocellular Carcinoma Among Diabetic Patients in Asia. Medicine (Baltimore). 2015; 94(24):e1013. PMC: 4616544. DOI: 10.1097/MD.0000000000001013. View

12.

Dave S, Kaur N, Nanduri R, Dkhar H, Kumar A, Gupta P . Inhibition of adipogenesis and induction of apoptosis and lipolysis by stem bromelain in 3T3-L1 adipocytes. PLoS One. 2012; 7(1):e30831. PMC: 3265525. DOI: 10.1371/journal.pone.0030831. View

13.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

14.

Lilja J, Kivisto K, Neuvonen P . Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther. 1998; 64(5):477-83. DOI: 10.1016/S0009-9236(98)90130-8. View

15.

Gao Y, Xue J, Li X, Jia Y, Hu J . Metformin regulates osteoblast and adipocyte differentiation of rat mesenchymal stem cells. J Pharm Pharmacol. 2008; 60(12):1695-700. DOI: 10.1211/jpp.60/12.0017. View

16.

Zhang J, Tang H, Zhang Y, Deng R, Shao L, Liu Y . Identification of suitable reference genes for quantitative RT-PCR during 3T3-L1 adipocyte differentiation. Int J Mol Med. 2014; 33(5):1209-18. DOI: 10.3892/ijmm.2014.1695. View

17.

Salvatore T, Pafundi P, Galiero R, Rinaldi L, Caturano A, Vetrano E . Can Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects?. Biomedicines. 2020; 9(1). PMC: 7822116. DOI: 10.3390/biomedicines9010003. View

18.

Kim B, Han S, Lee H, Park C, Chung Y, Shin K . Metformin enhances the anti-adipogenic effects of atorvastatin via modulation of STAT3 and TGF-β/Smad3 signaling. Biochem Biophys Res Commun. 2014; 456(1):173-8. DOI: 10.1016/j.bbrc.2014.11.054. View

19.

Simu S, Ahn S, Castro-Aceituno V, Yang D . Ginsenoside Rg5: Rk1 Exerts an Anti-obesity Effect on 3T3-L1 Cell Line by the Downregulation of PPARγ and CEBPα. Iran J Biotechnol. 2018; 15(4):252-259. PMC: 5903912. DOI: 10.15171/ijb.1517. View

20.

de Oliveira M, Mathias L, De Sibio M, Noronha-Matos J, Costa M, Nogueira C . Pitfalls and challenges of the purinergic signaling cascade in obesity. Biochem Pharmacol. 2020; 182:114214. DOI: 10.1016/j.bcp.2020.114214. View