The spontaneously hypertensive rat (SHR) is a widely used model of essential hypertension that also exhibits metabolic disturbances under specific conditions. Oxidative stress plays a central role in the pathogenesis of both hypertension and metabolic dysfunction, with the transcription factor Nrf2 regulating key antioxidant defenses. Here, we examined whether Nrf2 overexpression in the SHR improves adipose tissue metabolism. A mouse Nrf2 transgene under a universal promoter was markedly overexpressed in white adipose tissue, leading to increased insulin sensitivity, reduced saturated fatty acids, and higher n-3 polyunsaturated fatty acids in adipose membrane phospholipids. Transgenic rats also displayed reduced mitochondrial complex I levels, enhanced antioxidant enzyme activities, and decreased lipoperoxidation. Transcriptomic analysis revealed downregulation of oxidative phosphorylation genes. These findings suggest that Nrf2 overexpression confers antidiabetic and hypolipidemic effects in the SHR, potentially via redox-sensitive remodeling of adipose tissue metabolism. Key words: Nrf2 o Spontaneously hypertensive rat (SHR) o Oxidative stress o Adipose tissue o Metabolism o Mitochondrial function o Oxidative phosphorylation o Antioxidant defense o Insulin sensitivity o Fatty acids o transcriptomics o Transgenic rats o Gene expression.

stitute of Physiology Czech Academy of Sciences Prague Czech Republic

Zobrazit více v PubMed

Elnakish MT, Hassanain HH, Janssen PML, Angelos MG, Khan M. Emerging role of oxidative stress in metabolic syndrome and cardiovascular diseases: important role of Rac/NADPH oxidase. J Pathol. 2013;231:290–300. doi: 10.1002/path.4235. PubMed DOI

Roberts CK, Sindhu KK. Oxidative stress and metabolic syndrome. Life Sciences. 2009;84:705–712. doi: 10.1016/j.lfs.2009.02.026. PubMed DOI

Niture SK, Khatri R, Jaiswal AK. Regulation of Nrf2-an update. Free Rad Biol Med. 2014;66:36–44. doi: 10.1016/j.freeradbiomed.2013.02.008. PubMed DOI PMC

Zoccarato A, Smyrnias I, Reumiller CM, Hafstad AD, Chong M, Richards DA, et al. NRF2 activation in the heart induces glucose metabolic reprogramming and reduces cardiac dysfunction via upregulation of the pentose phosphate pathway. Cardiovasc Res. 2024;121:339–352. doi: 10.1093/cvr/cvae250. PubMed DOI PMC

Luchkova A, Mata A, Cadenas S. Nrf2 as a regulator of energy metabolism and mitochondrial function. FEBS Lett. 2024;598:2092–2105. doi: 10.1002/1873-3468.14993. PubMed DOI

Ludtmann MHR, Angelova PR, Zhang Y, Abramov AY, Dinkova-Kostova AT. Nrf2 affects the efficiency of mitochondrial fatty acid oxidation. Biochem J. 2014;457:415–424. doi: 10.1042/BJ20130863. PubMed DOI PMC

Kamisako T, Tanaka Y, Kishino Y, Ikeda T, Yamamoto K, Masuda S, et al. Role of Nrf2 in the alteration of cholesterol and bile acid metabolism-related gene expression by dietary cholesterol in high fat-fed mice. J Clin Biochem Nutr. 2014;54:90–94. doi: 10.3164/jcbn.13-92. PubMed DOI PMC

Li S, Eguchi N, Lau H, Cohen P. The role of the Nrf2 signaling in obesity and insulin resistance. Internat J Mol Sci. 2020;21:6973. doi: 10.3390/ijms21186973. PubMed DOI PMC

Guerrero-Beltrán CE. Anti-obesity effects of sulforaphane in a model of diet-induced obesity are mediated by the antioxidant response element. Exp Toxicol Pathol. 2012;64:503–508. doi: 10.1016/j.etp.2010.11.005. PubMed DOI

Chartoumpekis DV, Ziros PG, Psyrogiannis AI, Papavassiliou AG, Kensler TW, Sykiotis GP. Nrf2 represses FGF21 during long-term high-fat diet-induced obesity in mice. Diabetes. 2011;60:2465–2473. doi: 10.2337/db11-0112. PubMed DOI PMC

Chartoumpekis DV, Palliyaguru DL, Wakabayashi N, Fazzari M, Khoo NKH, Schopfer FJ, et al. Nrf2 deletion from adipocytes, but not hepatocytes, potentiates systemic metabolic dysfunction after long-term high-fat diet-induced obesity in mice. Am J Physiol-Endocrinol Metabolism. 2018;315:E180–E195. doi: 10.1152/ajpendo.00024.2018. PubMed DOI PMC

Xu J, Kulkarni SR, Donepudi AC, More VR, Slitt AL. Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice. Diabetes. 2012;61:3208–3218. doi: 10.2337/db11-1716. PubMed DOI PMC

Zhang YK, Wu KC, Liu J, Klaassen CD. Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. Toxicol Appl Pharmacol. 2012;264:305–314. doi: 10.1016/j.taap.2012.08.015. PubMed DOI PMC

Pravenec M, Zídek V, Landa V, Šimáková M, Křen V, Kazdová L, et al. Genetic analysis of “metabolic syndrome” in the spontaneously hypertensive rat. Physiol Res. 2004;53(Suppl 1):S15–S22. doi: 10.33549/physiolres.930000.53.S15. PubMed DOI

Malínská H, Oliyarnyk O, Hubová M, Škop V, Kazdová L, Vítek L, et al. Increased liver oxidative stress and altered PUFA metabolism precede development of non-alcoholic steatohepatitis in SREBP-1a transgenic spontaneously hypertensive rats with genetic predisposition to hepatic steatosis. Mol Cell Biochem. 2010;335:119–125. doi: 10.1007/s11010-009-0246-7. PubMed DOI

Pravenec M, Churchill PC, Churchill MC, Petretto E, Hubner N, Wallace CA, et al. Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension. Nat Genetics. 2008;40:952–954. doi: 10.1038/ng.164. PubMed DOI

Pravenec M, Kajiya T, Zídek V, Landa V, Mlejnek P, Šimáková M, et al. Effects of human C-reactive protein on pathogenesis of features of the metabolic syndrome. Hypertension. 2011;57:731–737. doi: 10.1161/HYPERTENSIONAHA.110.164350. PubMed DOI PMC

Pravenec M, Kožich V, Krijt J, Sokolová J, Zídek V, Landa V, et al. Folate deficiency is associated with oxidative stress, increased blood pressure, and insulin resistance in spontaneously hypertensive rats. Am J Hypertens. 2013;26:135–140. doi: 10.1093/ajh/hps006. PubMed DOI PMC

Houštek J, Hejzlarová K, Vrbacký M, Mŕček T, Drahota Z, Houštťkov́ H, et al. Nonsynonymous variants in mtNd2, mt-Nd4, and mt-Nd5 are linked to effects on oxidative phosphorylation and insulin sensitivity in rat conplastic strains. Physiol Genomics. 2012;44:487–494. doi: 10.1152/physiolgenomics.00170.2011. PubMed DOI PMC

Houštěk J, Vrbacký M, Hejzlarová K, Drahota Z, Kovalčíková J, Tauchmannová K, et al. Effects of mtDNA in SHR-mtF344 versus SHR conplastic strains on reduced OXPHOS enzyme levels, insulin resistance, cardiac hypertrophy, and systolic dysfunction. Physiol Genomics. 2014;46:671–678. doi: 10.1152/physiolgenomics.00140.2013. PubMed DOI

Pravenec M, Hyakukoku M, Houštěk J, Zídek V, Landa V, Mlejnek P, et al. Direct linkage of mitochondrial genome variation to risk factors for type 2 diabetes in conplastic strains. Genome Res. 2007;17:1319–1326. doi: 10.1101/gr.6004607. PubMed DOI PMC

Kuda O, Březinová M, Šilhavý J, Landa V, Zídek V, Pravenec M, et al. Nrf2-mediated antioxidant defense and peroxiredoxin 6 are linked to biosynthesis of palmitic acid ester of 9-hydroxystearic acid. Diabetes. 2018;67:1190–1199. doi: 10.2337/db17-1087. PubMed DOI PMC

Fan J, Ye J, Kaminski N, Dolganov GM, Zabner J, Hogg JC, et al. Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats. Am J Physiol-Lung Cell Mol Physiol. 2013;305:L267–L277. doi: 10.1152/ajplung.00288.2012. PubMed DOI PMC

Ivics Z, Mátés L, Yau TY, Landa V, Zidek V, Bashir S, et al. Transposon-mediated germline transgenesis in rodents. Nat Protocols. 2014;9:773–793. doi: 10.1038/nprot.2014.049. PubMed DOI

Miklánková D, Marková I, Hüttl M, Oliyarnyk O, Škop V, Kazdová L, et al. Metformin affects cardiac arachidonic acid metabolism and cardiac lipid metabolite storage in a prediabetic rat model. Internat J Mol Sci. 2021;22:7680. doi: 10.3390/ijms22147680. PubMed DOI PMC

Smyth GK. Limma: linear models for microarray data. In: Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W, editors. Bioinformatics and computational biology solutions using R and bioconductor. New York: Springer; 2005. pp. 397–420. DOI

Storey JD. The positive false discovery rate: a Bayesian interpretation and the q-value. Ann Statistics. 2003;31:2013–2035. doi: 10.1214/aos/1074290335. DOI

Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5:R80. doi: 10.1186/gb-2004-5-10-r80. PubMed DOI PMC

Kanehisa M, Goto S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acid Res. 2000;28:27–30. doi: 10.1093/nar/28.1.27. PubMed DOI PMC

Tian L, Greenberg SA, Kong SW, Altschuler J, Kohane IS, Park PJ. Discovering statistically significant pathways in expression profiling studies. Proc Nat Acad Sci USA. 2005;102:13544–13549. doi: 10.1073/pnas.0506577102. PubMed DOI PMC

Subramanian A, Tamayo P, Mootha VK, Jill P. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Nat Acad Sci USA. 2005;102:15545–15550. doi: 10.1073/pnas.0506580102. PubMed DOI PMC

Flachs P, Rossmeisl M, Bryhn M, Kopecky J. Cellular and molecular effects of n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci. 2009;116:1–16. doi: 10.1042/CS20070456. PubMed DOI

Ma Q. Role of Nrf2 in oxidative stress and toxicity. Annual Rev Pharmacol Toxicol. 2013;53:401–426. doi: 10.1146/annurev-pharmtox-011112-140320. PubMed DOI PMC

Vernochet C, Damilano F, Mourier A, Bezy O, Mori MA, Smyth G, et al. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. FASEB Journal. 2014;28:4408–4419. doi: 10.1096/fj.14-253971. PubMed DOI PMC

Kusminski CM, Scherer PE. Mitochondrial dysfunction in white adipose tissue. Trend Endocrinol Metab. 2012;23:435–443. doi: 10.1016/j.tem.2012.06.004. PubMed DOI PMC

Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22:66–79. doi: 10.1016/j.ccr.2012.05.016. PubMed DOI

Piantadosi CA, Carraway MS, Babiker A, Suliman HB. Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res. 2008;103:1238–1246. doi: 10.1161/CIRCRESAHA.108.176321. PubMed DOI PMC

Schneider K, Valdez J, Nguyen J, Vawter M, Galke B, Kurtz TW, et al. Increased energy expenditure, Ucp1 expression, and resistance to diet-induced obesity in mice lacking nuclear factor-erythroid-2-related transcription factor-2 (Nrf2) J Biol Chem. 2016;291:7754–7766. doi: 10.1074/jbc.M115.673756. PubMed DOI PMC

Zhang YK, Wu KC, Liu J, Klaassen CD. Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. Toxicol Applied Pharmacol. 2012;264:305–314. doi: 10.1016/j.taap.2012.09.014. PubMed DOI PMC

Xue P, Hou Y, Chen Y, Yang B, Fu J, Zheng H, et al. Adipose deficiency of Nrf2 in ob/ob mice results in severe metabolic syndrome. Diabetes. 2013;62:845–854. doi: 10.2337/db12-0584. PubMed DOI PMC