Resveratrol Stabilizes Cytosolic ß-Catenin Through The Activation of The Thermogenic Cascade

Abstract

Resveratrol Stabilizes Cytosolic ß-Catenin Through The Activation of The Thermogenic Cascade

Abstract

Purpose: Resveratrol is a polyphenolic compound that has been shown to stimulate fatty acid oxidation and increase the expression of genes associated with thermogenic processes. Therefore, it is important to investigate the effects of resveratrol beyond intracellular thermogenic pathways to determine side effects at the cellular level. The aim of this study was to evaluate the effect of resveratrol on intracellular ß-catenin, in addition to its thermogenic effect. Materials and methods: The effect of resveratrol on thermogenic genes such as SIRT1 gene, UCP1, PGC1α, PRDM16 and ß-catenin gene expression levels was analyzed by RT-PCR. The cytosolic ß-catenin level analyzed by western-blot. Results: The effect of resveratrol on thermogenic genes such as SIRT1 gene, UCP1, PGC1α, PRDM16 and ß-catenin gene expression levels was analyzed by RT-PCR. The cytosolic ß-catenin level analyzed by western-blot. We found that the expression levels of UCP1, PPARγ, PRDM16 were increased by SIRT1 protein activated by resveratrol, but it had no effect on ß-catenin mRNA expression. While ß-catenin did not change at the mRNA level, we found that ß-catenin increased at the protein level in the cell independently of the canonical Wnt pathway. Conclusion: Our results suggest that resveratrol, which is widely used as a supplement, may also act on different signaling pathways in the cell.

Keywords

• resveratrol
• obesity
• thermogenesis
• β-Catenin

References

1. Dos Santos TW, Pereira QC, Teixeira L, Gambero A, Villena JA, Ribeiro ML. Effects of Polyphenols on Thermogenesis and Mitochondrial Biogenesis. Int J Mol Sci 2018;19.
2. Park A, Kim WK, Bae K-H. Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells. World J Stem Cells 2014;6:33.
3. Bartelt A, Widenmaier SB. Proteostasis in thermogenesis and obesity. Biol Chem 2020;401:1019–30.
4. Saely CH, Geiger K, Drexel H. Brown versus white adipose tissue: a mini-review. Gerontology 2012;58:15–23.
5. Kuryłowicz A, Puzianowska-Kuźnicka M. Induction of Adipose Tissue Browning as a Strategy to Combat Obesity. Int J Mol Sci 2020;21:1–28.
6. Liu RH. Dietary Bioactive Compounds and Their Health Implications. J Food Sci 2013;78:A18–25.
7. Wang S, Zhu MJ, Du M. Prevention of obesity by dietary resveratrol: how strong is the evidence? Expert Rev Endocrinol Metab 2015;10:561–4.
8. de Ligt M, Timmers S, Schrauwen P. Resveratrol and obesity: Can resveratrol relieve metabolic disturbances? Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2015;1852:1137–44.

9. Li X. SIRT1 and energy metabolism. Acta Biochim Biophys Sin (Shanghai) 2013;45:51–60.
10. Gut P, Verdin E. Rejuvenating SIRT1 activators. Cell Metab 2013;17:635–7.
11. Yamamoto H, Schoonjans K, Auwerx J. Sirtuin functions in health and disease. Mol Endocrinol 2007;21:1745–55.
12. Azhar Y, Parmar A, Miller CN, Samuels JS, Rayalam S. Phytochemicals as novel agents for the induction of browning in white adipose tissue. Nutr Metab (Lond) 2016;13.
13. Pan MH, Koh YC, Lee TL, Wang B, Chen WK, Nagabhushanam K, et al. Resveratrol and Oxyresveratrol Activate Thermogenesis via Different Transcriptional Coactivators in High-Fat Diet-Induced Obese Mice. J Agric Food Chem 2019;67:13605–16.
14. Jiang N, Yang M, Han Y, Zhao H, Sun L. PRDM16 Regulating Adipocyte Transformation and Thermogenesis: A Promising Therapeutic Target for Obesity and Diabetes. Front Pharmacol 2022;13.
15. Emont MP, Kim D il, Wu J. Development, activation, and therapeutic potential of thermogenic adipocytes. Biochim Biophys Acta Mol Cell Biol Lipids 2019;1864:13–9.
16. Prestwich TC, MacDougald OA. Wnt/β-catenin signaling in adipogenesis and metabolism. Curr Opin Cell Biol 2007;19:612.
17. Dai H, Deng HB, Wang YH, Guo JJ. Resveratrol inhibits the growth of gastric cancer via the Wnt/β-catenin pathway. Oncol Lett 2018;16:1579–83.
18. Reed BC, Lane MD. Insulin receptor synthesis and turnover in differentiating 3T3-L1 preadipocytes. Proc Natl Acad Sci U S A 1980;77:285–9.
19. Imamura H, Nagayama D, Ishihara N, Tanaka S, Watanabe R, Watanabe Y, et al. Resveratrol attenuates triglyceride accumulation associated with upregulation of Sirt1 and lipoprotein lipase in 3T3-L1 adipocytes. Mol Genet Metab Rep 2017;12:44–50.
20. Mayoral R, Osborn O, McNelis J, Johnson AM, Oh DY, Izquierdo CL, et al. Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. Mol Metab 2015;4:378.
21. Elibol B, Kilic U. High Levels of SIRT1 Expression as a Protective Mechanism Against Disease-Related Conditions. Front Endocrinol (Lausanne) 2018;9.
22. Lo KA, Sun L. Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes. Biosci Rep 2013;33:711–9.
23. Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell 2012;150:620–32.
24. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998;92:829–39.
25. Liu Z, Liao W, Yin X, Zheng X, Li Q, Zhang H, et al. Resveratrol-induced brown fat-like phenotype in 3T3-L1 adipocytes partly via mTOR pathway. Food Nutr Res 2020;64.
26. Mineda A, Nishimura M, Kagawa T, Takiguchi E, Kawakita T, Abe A, et al. Resveratrol suppresses proliferation and induces apoptosis of uterine sarcoma cells by inhibiting the Wnt signaling pathway. Exp Ther Med 2019;17.
27. Liu H, Zhang X, Fang C, Li S. Resveratrol induces the growth inhibition of CDX-deficient gastric cancer cells using CDX2 and RUNX3 via the β-catenin/TCF4 signaling pathway. Transl Oncol 2023;35.
28. Chen X, Sun S, Geng T, Fan X, Zhang S, Zhao S, et al. Resveratrol reduces the progression of titanium particle-induced osteolysis via the Wnt/β-catenin signaling pathway in vivo and in vitro. Exp Ther Med 2021;22.
29. Yang M, Li Z, Tao J, Hu H, Li Z, Zhang Z, et al. Resveratrol induces PD-L1 expression through snail-driven activation of Wnt pathway in lung cancer cells. J Cancer Res Clin Oncol 2021;147:1101–13.
30. Zhou Y, Song T, Peng J, Zhou Z, Wei H, Zhou R, et al. SIRT1 suppresses adipogenesis by activating Wnt/β-catenin signaling in vivo and in vitro. Oncotarget 2016;7:77707–20.