Obesity, defined with a BMI ≥ 30.0 kg/m2, affects over 40% of U.S. adults. Although dieting or surgery are possible, majority of treatments have consequential side effects. Recent studies have found increased energy expenditure in white adipocytes via lipolysis of fat droplets that may lead to weight loss induced by catecholamines, which are neurotransmitters. However, it is associated with mitochondrial depolarization that is linked to apoptosis, causing lipotoxicity and further complications. Studies have found that curcumin, an antioxidant, can alleviate mitochondrial depolarization through the mitochondrial membrane permeability transition pore (mPTP), a transmembrane protein, but has not been studied in adipocytes. Therefore, this study investigated the role of mPTP opening in membrane depolarization and antioxidant properties of curcumin in catecholamine-stimulated white adipocytes. Preadipocytes isolated from C57Bl/6 wild type male mice were differentiated. Oxygen consumption rate (OCR) and normalized intensity measuring membrane potential were measured using seahorse assays and tetramethylrhodamine methyl ester (TMRM) dye imaging, respectively. Results revealed normalized intensity with addition of mPTP inhibitor cyclosporine A (CSA) was significantly higher than CL-316,243 Control (p<0.05), suggesting that inhibition of mPTP can alleviate membrane potential loss. However, Alleviating Mitochondrial Depolarization With Inhibition of mPTP in CatecholamineStimulated White Adipocytes Serena Chen addition of CSA still decreased mitochondrial membrane intensity, suggesting mPTP opening only plays a partial role in membrane depolarization. Results also found 24-hour curcumin pretreatment had significantly increased OCR at its peak compared to V Curcumin (p<0.0001), suggesting curcumin may increase energy expenditure. However, curcumin did not prevent mitochondrial dysfunction as observed with steady OCR decline.

References

1. Alexander, E., Selwyn, A., Calitz, C., Yach, D., & Wang, Y. C. (2016). Obesity: Causes and prevalence. In Encyclopedia of Food and Health, 132–138. https://doi.org/10.1016/B978-0-12-384947-2.00500-6
2. Sanders, M. H., & Givelber, R. (2006). Obesity. In Encyclopedia of Respiratory Medicine, 181–185. https://doi.org/10.1016/B0-12-370879-6/00268-4
3. Bolling, C. F., & Daniels, S. R. (2008). Obesity. In Encyclopedia of Infant and Early Childhood Development, 461–468. https://doi.org/10.1016/B978-012370877-9.00114-6
4. Alexopoulos, S. J., et al. (2020). Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice. Nature Communications, 11, 2397. https://doi.org/10.1038/s41467-020-16298-2
5. Kanemoto, N., et al. (2019). Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler. Nature Communications, 10, 2172. https://doi.org/10.1038/s41467-019-09911-6
6. Izem-Meziane, M., et al. (2011). Catecholamine-induced cardiac mitochondrial dysfunction and mPTP opening: protective effect of curcumin. American Journal of Physiology, 302(3), 665–674. https://doi.org/10.1152/ajpheart.00467.2011
7. Othumpangat, S. (2014). Catecholamines. In Encyclopedia of Toxicology, 748–750. https://doi.org/10.1016/B978-0-12-386454-3.00271-2
8. Reilly, S. M., et al. (2020). Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3. Nature Metabolism, 2(7), 620–634. https://doi.org/10.1038/s42255-020-0217-6
9. Yehuda-Shnaidman, E., et al. (2010). Acute stimulation of white adipocyte respiration by PKA-induced lipolysis. Diabetes, 59(10), 2474–2483. https://doi.org/10.2337/db10-0245
10. Harper, J. A., Dickinson, K., & Brand, M. D. (2001). Mitochondrial uncoupling as a target for drug development for the treatment of obesity. Obesity Reviews, 2(4), 255–265. https://doi.org/10.1046/j.1467-789x.2001.00043.x
11. Demine, S., Renard, P., & Arnould, T. (2019). Mitochondrial uncoupling: A key controller of biological processes in physiology and diseases. Cells, 8(8), 795. https://doi.org/10.3390/cells8080795
12. Zorova, L. D., et al. (2018). Mitochondrial membrane potential. Analytical Biochemistry, 552, 50–59. https://doi.org/10.1016/j.ab.2017.07.009
13. Cohen, P., & Kajimura, S. (2021). The cellular and functional complexity of thermogenic fat. Nature Reviews Molecular Cell Biology, 22(6), 393–409. https://doi.org/10.1038/s41580-021-00350-0
14. Banks, M. A. (2022). Brown fat holds promise for addressing obesity and a host of related ills. PNAS, 119(43), e2216435119. https://doi.org/10.1073/pnas.2216435119
15. Pan, R., Zhu, X., Maretich, P., & Chen, Y. (2020). Combating obesity with thermogenic fat: Current challenges and advancements. Frontiers in Endocrinology, 11, 185. https://doi.org/10.3389/fendo.2020.00185
16. Fiorillo, C., et al. (2008). Curcumin protects cardiac cells against ischemia-reperfusion injury. Free Radical Biology & Medicine, 45(6), 839–846. https://doi.org/10.1016/j.freeradbiomed.2008.06.013
17. Ansari, M. N., et al. (2007). Protective role of curcumin in myocardial oxidative damage induced by isoproterenol in rats. Human & Experimental Toxicology, 26(12), 933–938. https://doi.org/10.1177/0960327107085835
18. Tanwar, V., et al. (2010). Curcumin protects rat myocardium against isoproterenol-induced ischemic injury. Journal of Cardiovascular Pharmacology, 55(4), 377–384. https://doi.org/10.1097/FJC.0b013e3181d3da01
19. Shirmard, L. R., et al. (2022). Protective effect of curcumin, chrysin and thymoquinone injection on trastuzumab-induced cardiotoxicity via mitochondrial protection. Cardiovascular Toxicology, 22, 663–675. https://doi.org/10.1007/s12012-022-09750-w
20. Wang, S., et al. (2015). Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way. Biochemical and Biophysical Research Communications, 466(2), 247–253. https://doi.org/10.1016/j.bbrc.2015.09.018
21. Peris, E., et al. (2018). Antioxidant treatment induces reductive stress associated with mitochondrial dysfunction in adipocytes. Journal of Biological Chemistry, 294(7), 2340–2352. https://doi.org/10.1074/jbc.RA118.004253
22. Chen, H. W., et al. (2002). Cyclosporine A regulates oxidative stress-induced apoptosis in cardiomyocytes. British Journal of Pharmacology, 137(6), 771–781. https://doi.org/10.1038/sj.bjp.0704908