BACKGROUND: Quercetin is a promising phytochemical in treating abnormalities associated with metabolic syndrome (MetS). This study aimed to explore the morphometric, metabolic, transcriptomic, and nutrigenetic responses to quercetin supplementation using two genetically distinct MetS models that only differ in the variant of the MetS-related Zbtb16 gene (Zinc Finger And BTB Domain Containing 16). RESULTS: Quercetin supplementation led to a significant reduction in the relative weight of retroperitoneal adipose tissue in both investigated strains. A decrease in visceral (epididymal) fat mass, accompanied by an increase in brown fat mass after quercetin treatment, was observed exclusively in the SHR strain. While the levels of serum triglycerides decreased within both strains, the free fatty acids levels decreased in SHR-Zbtb16-Q rats only. The total serum cholesterol levels were not affected by quercetin in either of the two tested strains. While there were no significant changes in brown adipose tissue transcriptome, quercetin supplementation led to a pronounced gene expression shift in white retroperitoneal adipose tissue, particularly in SHR-Zbtb16-Q. CONCLUSION: Quercetin administration ameliorates certain MetS-related features; however, the efficacy of the treatment exhibits subtle variations depending on the specific variant of the Zbtb16 gene.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Prague Czech Republic

Institute of Biology and Medical Genetics the 1st Faculty of Medicine Charles University General University Hospital Prague Albertov 4 Prague 2 128 00 Czech Republic

Zobrazit více v PubMed

Rochlani Y, Pothineni NV, Kovelamudi S, Mehta JL. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther Adv Cardiovasc Dis. 2017;11(8):215–25. PubMed DOI PMC

Bovolini A, Garcia J, Andrade MA, Duarte JA. Metabolic syndrome pathophysiology and predisposing factors. Int J Sports Med. 2021;42(3):199–214. PubMed DOI

Mendrick DL, Diehl AM, Topor LS, Dietert RR, Will Y, La Merrill MA, et al. Metabolic syndrome and Associated diseases: from the bench to the clinic. Toxicol Sci. 2018;162(1):36–42. PubMed DOI PMC

Punthakee Z, Goldenberg R, Katz P, Definition. Classification and diagnosis of diabetes, prediabetes and metabolic syndrome. Can J Diabetes. 2018;42:S10–5. PubMed DOI

Wang HH, Lee DK, Liu M, Portincasa P, Wang DQ. Novel insights into the Pathogenesis and management of the metabolic syndrome. Pediatr Gastroenterol Hepatol Nutr. 2020;23(3):189–230. PubMed DOI PMC

Després J-P. Abdominal obesity: the most prevalent cause of the metabolic syndrome and related cardiometabolic risk. Eur Heart J Supplements. 2006;8(supplB):B4–12. DOI

Després JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, et al. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol. 2008;28(6):1039–49. PubMed DOI

Fahed G, Aoun L, Bou Zerdan M, Allam S, Bouferraa Y, Assi HI. Metabolic syndrome: updates on pathophysiology and management in 2021. Int J Mol Sci. 2022;23(2). PubMed PMC

Xu H, Li X, Adams H, Kubena K, Guo S. Etiology of metabolic syndrome and dietary intervention. Int J Mol Sci. 2018;20(1). PubMed PMC

Hirode G, Wong RJ. Trends in the prevalence of metabolic syndrome in the United States, 2011–2016. JAMA. 2020;323(22):2526–8. 10.1001/jama.2020.4501. PubMed DOI PMC

Lillich FF, Imig JD, Proschak E. Multi-target approaches in metabolic syndrome. Front Pharmacol. 2021;11:1996. PubMed DOI PMC

Anand David AV, Arulmoli R, Parasuraman S. Overviews of Biological Importance of Quercetin: a bioactive flavonoid. Pharmacogn Rev. 2016;10(20):84–9. PubMed DOI PMC

Huang H, Liao D, Dong Y, Pu R. Effect of quercetin supplementation on plasma lipid profiles, blood pressure, and glucose levels: a systematic review and meta-analysis. Nutr Rev. 2020;78(8):615–26. PubMed DOI

Salehi B, Machin L, Monzote L, Sharifi-Rad J, Ezzat SM, Salem MA, et al. Therapeutic potential of Quercetin: New insights and perspectives for Human Health. Acs Omega. 2020;5(20):11849–72. PubMed DOI PMC

Aghababaei F, Hadidi M. Recent advances in potential health benefits of Quercetin. Pharmaceuticals (Basel). 2023;16(7). PubMed PMC

Hosseini A, Razavi BM, Banach M, Hosseinzadeh H. Quercetin and metabolic syndrome: a review. Phytother Res. 2021;35(10):5352–64. PubMed DOI

Yi H, Peng H, Wu X, Xu X, Kuang T, Zhang J, et al. The therapeutic effects and mechanisms of Quercetin on metabolic diseases: Pharmacological Data and clinical evidence. Oxidative Med Cell Longev. 2021;2021:6678662. PubMed DOI PMC

Jin Y, Nenseth HZ, Saatcioglu F. Role of PLZF as a tumor suppressor in prostate cancer. Oncotarget. 2017;8(41):71317–24. PubMed DOI PMC

Liu TM, Lee EH, Lim B, Shyh-Chang N. Concise Review: balancing Stem Cell Self-Renewal and differentiation with PLZF. Stem Cells. 2016;34(2):277–87. PubMed DOI

Šeda O, Šedová L, Včelák J, Vaňková M, Liška F, Bendlová B. ZBTB16 and metabolic syndrome: a network perspective. Physiol Res. 2017;66(Suppl 3):S357–65. PubMed DOI

Bendlova B, Vankova M, Hill M, Vacinova G, Lukasova P, VejraZkova D, et al. ZBTB16 gene variability influences obesity-related parameters and serum lipid levels in Czech adults. Physiol Res. 2017;66(Supplementum 3):S425–31. PubMed DOI

Wei S, Zhang M, Zheng Y, Yan P. ZBTB16 overexpression enhances white adipogenesis and induces Brown-Like Adipocyte formation of bovine White Intramuscular Preadipocytes. Cells Tissues Organs. 2019;207(2):88–101. 10.1159/000492697. PubMed DOI

Hu H, Sun N, Du H, He Y, Pan K, Liu X, et al. Mouse promyelocytic leukemia zinc finger protein (PLZF) regulates hepatic lipid and glucose homeostasis dependent on SIRT1. Front Pharmacol. 2022;13:1039726. PubMed DOI PMC

Chen S, Qian J, Shi X, Gao T, Liang T, Liu C. Control of hepatic gluconeogenesis by the promyelocytic leukemia zinc finger protein. Mol Endocrinol. 2014;28(12):1987–98. PubMed DOI PMC

Kwitek AE. Rat models of metabolic syndrome. Methods Mol Biol. 2019;2018:269–85. PubMed DOI PMC

Školníková E, Šedová L, Chylíková B, Kábelová A, Liška F, Šeda O. Maternal high-sucrose Diet affects phenotype outcome in adult male offspring: role of Zbtb16. Front Genet. 2020;11:529421. 10.3389/fgene.2020.529421. PubMed DOI PMC

Kábelová A, Krupková M, Kazdová L, Šedová L, Křenová D, Liška F, et al. The effect of Zbtb16 gene on insulin sensitivity and lipid levels revealed by a single-gene congenic rat model. Atherosclerosis. 2017;263. 10.1016/j.atherosclerosis.2017.06.895.

Vedi M, Smith JR, Thomas Hayman G, Tutaj M, Brodie KC, De Pons JL et al. 2022 updates to the rat genome database: a findable, accessible, interoperable, and Reusable (FAIR) resource. Genetics. 2023;224(1). PubMed PMC

Liška F, Mancini M, Krupková M, Chylíková B, Křenová D, Šeda O, et al. Plzf as a candidate gene predisposing the spontaneously hypertensive rat to hypertension, left ventricular hypertrophy, and interstitial fibrosis. Am J Hypertens. 2014;27(1):99–106. PubMed DOI

Krupková M, Liška F, Kazdová L, Šedová L, Kábelová A, Křenová D, et al. Single-gene congenic strain reveals the effect of Zbtb16 on metabolic syndrome-related traits. Front Endocrinol (Lausanne). 2018;9:185. 10.3389/fendo.2018.00185. PubMed DOI PMC

Cahova M, Dankova H, Palenickova E, Papackova Z, Kazdova L. The opposite effects of high-sucrose and high-fat diet on fatty acid oxidation and very low density lipoprotein secretion in rat model of metabolic syndrome. J Nutr Metab. 2012;2012:757205. PubMed DOI PMC

Panchal SK, Poudyal H, Brown L. Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats. J Nutr. 2012;142(6):1026–32. PubMed DOI

Kábelová A, Malínská H, Marková I, Hűttl M, Chylíková B, Šeda O. Quercetin supplementation alters adipose tissue and hepatic transcriptomes and ameliorates adiposity, dyslipidemia, and glucose intolerance in adult male rats. Front Nutr. 2022;9:952065. PubMed DOI PMC

Krämer A, Green J, Pollard J, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014;30(4):523–30. PubMed DOI PMC

Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44(W1):W90–7. PubMed DOI PMC

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402–8. PubMed DOI

Scholze J, Alegria E, Ferri C, Langham S, Stevens W, Jeffries D, et al. Epidemiological and economic burden of metabolic syndrome and its consequences in patients with hypertension in Germany, Spain and Italy; a prevalence-based model. BMC Public Health. 2010;10(1):529. PubMed DOI PMC

Aguilar M, Bhuket T, Torres S, Liu B, Wong RJ. Prevalence of the metabolic syndrome in the United States, 2003–2012. Jama-Journal Am Med Association. 2015;313(19):1973–4. PubMed DOI

Bitew ZW, Alemu A, Ayele EG, Tenaw Z, Alebel A, Worku T. Metabolic syndrome among children and adolescents in low and middle income countries: a systematic review and meta-analysis. Diabetol Metab Syndr. 2020;12:93. PubMed DOI PMC

Seo MJ, Lee YJ, Hwang JH, Kim KJ, Lee BY. The inhibitory effects of quercetin on obesity and obesity-induced inflammation by regulation of MAPK signaling. J Nutr Biochem. 2015;26(11):1308–16. PubMed DOI

Chen S, Jiang H, Wu X, Fang J. Therapeutic effects of Quercetin on inflammation, obesity, and type 2 diabetes. Mediat Inflamm. 2016;2016:9340637. PubMed DOI PMC

Zhao Y, Chen B, Shen J, Wan L, Zhu Y, Yi T, et al. The Beneficial effects of Quercetin, Curcumin, and resveratrol in obesity. Oxid Med Cell Longev. 2017;2017:1459497. PubMed DOI PMC

Ahn J, Lee H, Kim S, Park J, Ha T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun. 2008;373(4):545–9. PubMed DOI

Choi H, Kim CS, Yu R. Quercetin Upregulates uncoupling protein 1 in White/Brown adipose tissues through sympathetic stimulation. J Obes Metab Syndr. 2018;27(2):102–9. PubMed DOI PMC

Zhang X, Li X, Fang H, Guo F, Li F, Chen A, et al. Flavonoids as inducers of white adipose tissue browning and thermogenesis: signalling pathways and molecular triggers. Nutr Metab (Lond). 2019;16:47. PubMed DOI PMC

Michala AS, Pritsa A, Quercetin. A molecule of great biochemical and clinical value and its beneficial effect on diabetes and Cancer. Diseases. 2022;10(3):37. 10.3390/diseases10030037. PubMed DOI PMC

Perdicaro DJ, Rodriguez Lanzi C, Gambarte Tudela J, Miatello RM, Oteiza PI, Vazquez Prieto MA. Quercetin attenuates adipose hypertrophy, in part through activation of adipogenesis in rats fed a high-fat diet. J Nutr Biochem. 2020;79:108352. PubMed DOI

Wang SY, Duan KM, Li Y, Mei Y, Sheng H, Liu H, et al. Effect of quercetin on P-glycoprotein transport ability in Chinese healthy subjects. Eur J Clin Nutr. 2013;67(4):390–4. PubMed DOI

Duan KM, Wang SY, Ouyang W, Mao YM, Yang LJ. Effect of quercetin on CYP3A activity in Chinese healthy participants. J Clin Pharmacol. 2012;52(6):940–6. PubMed DOI

Braun JL, Geromella MS, Hamstra SI, Fajardo VA. Neuronatin regulates whole-body metabolism: is thermogenesis involved? FASEB Bioadv. 2020;2(10):579–86. PubMed DOI PMC

Choi KM, Ko CY, An SM, Cho SH, Rowland DJ, Kim JH, et al. Regulation of beige adipocyte thermogenesis by the cold-repressed ER protein NNAT. Mol Metab. 2023;69:101679. PubMed DOI PMC

Parrillo L, Spinelli R, Longo M, Desiderio A, Mirra P, Nigro C, et al. Altered hepatic SIRT6/AMPK pathway as a potential link between Diet and insulin resistance in non-alcoholic fatty liver disease. Epigenomics. 2020;12(10):873–88. 10.2217/epi-2019-0267. PubMed DOI

Benchoula K, Arya A, Parhar IS, Hwa WE. FoxO1 signaling as a therapeutic target for type 2 diabetes and obesity. Eur J Pharmacol. 2021;891:173758. PubMed DOI

Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci U S A. 2000;97(23):12729–34. PubMed DOI PMC

Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. Estrogens in male physiology. Physiol Rev. 2017;97(3):995–1043. PubMed DOI PMC

Kuipers EN, Dam ADV, Held NM, Mol IM, Houtkooper RH, Rensen PCN et al. Quercetin lowers plasma triglycerides accompanied by White Adipose tissue Browning in Diet-Induced obese mice. Int J Mol Sci. 2018;19(6). PubMed PMC

Jung CH, Cho I, Ahn J, Jeon TI, Ha TY. Quercetin reduces high-fat diet-induced fat accumulation in the liver by regulating lipid metabolism genes. Phytother Res. 2013;27(1):139–43. PubMed DOI

Hoek-van den Hil EF, van Schothorst EM, van der Stelt I, Swarts HJ, Venema D, Sailer M, et al. Quercetin decreases high-fat diet induced body weight gain and accumulation of hepatic and circulating lipids in mice. Genes Nutr. 2014;9(5):418. PubMed DOI PMC

Eid HM, Haddad PS. The antidiabetic potential of Quercetin: underlying mechanisms. Curr Med Chem. 2017;24(4):355–64. PubMed DOI

Al-Ishaq RK, Abotaleb M, Kubatka P, Kajo K, Büsselberg D. Flavonoids and their anti-diabetic effects: Cellular mechanisms and effects to Improve Blood Sugar levels. Biomolecules. 2019;9(9). PubMed PMC

Ansari P, Choudhury ST, Seidel V, Rahman AB, Aziz MA, Richi AE et al. Therapeutic potential of Quercetin in the management of Type-2 diabetes Mellitus. Life (Basel). 2022;12(8). PubMed PMC

Youl E, Bardy G, Magous R, Cros G, Sejalon F, Virsolvy A, et al. Quercetin potentiates insulin secretion and protects INS-1 pancreatic β-cells against oxidative damage via the ERK1/2 pathway. Br J Pharmacol. 2010;161(4):799–814. PubMed DOI PMC

Yan L, Vaghari-Tabari M, Malakoti F, Moein S, Qujeq D, Yousefi B et al. Quercetin: an effective polyphenol in alleviating diabetes and diabetic complications. Crit Rev Food Sci Nutr. 2022:1–24. PubMed

Dhanya R. Quercetin for managing type 2 diabetes and its complications, an insight into multitarget therapy. Biomed Pharmacother. 2022;146:112560. PubMed DOI

Paublini H, López González AA, Busquets-Cortés C, Tomas-Gil P, Riutord-Sbert P, Ramírez-Manent JI. Relationship between atherogenic dyslipidaemia and Lipid Triad and scales that assess insulin resistance. Nutrients. 2023;15(9). PubMed PMC

Musunuru K. Atherogenic dyslipidemia: cardiovascular risk and dietary intervention. Lipids. 2010;45(10):907–14. PubMed DOI PMC

Guo W, Gong X, Li M. Quercetin actions on lipid profiles in overweight and obese individuals: a systematic review and Meta-analysis. Curr Pharm Des. 2019;25(28):3087–95. PubMed DOI

Wang M, Wang B, Wang S, Lu H, Wu H, Ding M, et al. Effect of quercetin on lipids metabolism through modulating the gut microbial and AMPK/PPAR Signaling Pathway in Broilers. Front Cell Dev Biology. 2021;9:165. PubMed PMC