Menopause brings about profound physiological changes, including the acceleration of insulin resistance and other abnormalities, in which adipose tissue can play a significant role. This study analyzed the effect of ovariectomy and estradiol substitution on the metabolic parameters and transcriptomic profile of adipose tissue in prediabetic females of hereditary hypertriglyceridemic rats (HHTgs). The HHTgs underwent ovariectomy (OVX) or sham surgery (SHAM), and half of the OVX group received 17β-estradiol (OVX+E2) post-surgery. Ovariectomy resulted in weight gain, an impaired glucose tolerance, ectopic triglyceride (TG) deposition, and insulin resistance exemplified by impaired glycogenesis and lipogenesis. Estradiol alleviated some of the disorders associated with ovariectomy; in particular, it improved insulin sensitivity and reduced TG deposition. A transcriptomic analysis of perimetrial adipose tissue revealed 809 differentially expressed transcripts in the OVX vs. SHAM groups, mostly pertaining to the regulation of lipid and glucose metabolism, and oxidative stress. Estradiol substitution affected 1049 transcripts with overrepresentation in the signaling pathways of lipid metabolism. The principal component and hierarchical clustering analyses of transcriptome shifts corroborated the metabolic data, showing a closer resemblance between the OVX+E2 and SHAM groups compared to the OVX group. Changes in the adipose tissue transcriptome may contribute to metabolic abnormalities accompanying ovariectomy-induced menopause in HHTg females. Estradiol substitution may partially mitigate some of these disorders.

Centre for Experimental Medicine Institute for Clinical and Experimental Medicine 140 21 Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University and General University Hospital 121 08 Prague Czech Republic

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Jeong J.H., Park H. Metabolic disorders in menopause. Metabolites. 2022;12:954. doi: 10.3390/metabo12100954. PubMed DOI PMC

Hodis H.N., Mack W.J. Menopausal Hormone Replacement Therapy and Reduction of All-Cause Mortality and Cardiovascular Disease: It’s About Time and Timing. Cancer J. 2022;28:208–223. doi: 10.1097/PPO.0000000000000591. PubMed DOI PMC

Pu D., Tan R., Yu Q., Wu J. Metabolic syndrome in menopause and associated factors: A meta-analysis. Climacteric. 2017;20:583–591. doi: 10.1080/13697137.2017.1386649. PubMed DOI

Park Y.W., Zhu S., Palaniappan L., Heshka S., Carnethon M.R., Heymsfield S.B. The metabolic syndrome: Prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch. Intern. Med. 2003;163:427–436. doi: 10.1001/archinte.163.4.427. PubMed DOI PMC

Lombard L., Augustyn M.N., Ascott-Evans B.H. The metabolic syndrome-pathogenesis, clinical features and management. Cardiovasc. J. S. Afr. 2002;13:181–186. PubMed

Ribas V., Nguyen M.T.A., Henstridge D.C., Nguyen A.K., Beaven S.W., Watt M.J., Hevener A.L. Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice. Am. J. Physiol. Endocrinol. Metab. 2010;298:E304–E319. doi: 10.1152/ajpendo.00504.2009. PubMed DOI PMC

Tawfik S.H., Mahmoud B.F., Saad M.I., Shehata M., Kamel M.A., Helmy M.H. Similar and Additive Effects of Ovariectomy and Diabetes on Insulin Resistance and Lipid Metabolism. Biochem. Res. Int. 2015;2015:567945. doi: 10.1155/2015/567945. PubMed DOI PMC

Eaton S.A., Sethi J.K. Immunometabolic Links between Estroge, Adipose Tissue and Female Reproductive Metabolism. Biology. 2019;8:8. doi: 10.3390/biology8010008. PubMed DOI PMC

Kozakowski J., Gietka-Czernel M., Leszczyńska D., Majo A. Obesity in menopause—our negligence or an unfortunate inevitability? Menopause Rev. 2017;16:61–65. doi: 10.5114/pm.2017.68594. PubMed DOI PMC

Kawakami M., Yokota-Nakagi N., Uji M., Yoshida K.I., Tazumi S., Takamata A., Uchida Y., Morimoto K. Estrogen replacement enhances insulin-induced AS160 activation and improves insulin sensitivity in ovariectomized rats. Am. J. Physiol. Endocrinol. Metab. 2018;315:E1296–E1304. doi: 10.1152/ajpendo.00131.2018. PubMed DOI

Yokota-Nakagi N., Takahashi H., Kawakami M., Takamata A., Uchida Y., Morimoto K. Estradiol Replacement Improves High-Fat Diet-Induced Obesity by Suppressing the Action of Ghrelin in Ovariectomized Rats. Nutrients. 2020;12:907. doi: 10.3390/nu12040907. PubMed DOI PMC

Leeners B., Geary N., Tobler P.N., Asarian L. Ovarian hormones and obesity. Human. Reproduction Update. 2017;23:300–321. doi: 10.1093/humupd/dmw045. PubMed DOI PMC

Salpeter S.R., Walsh J.M.E., Ormiston T.M., Greyber E., Buckley N.S., Salpeter E.E. Meta-analysis: Effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes. Metab. 2006;8:538–554. doi: 10.1111/j.1463-1326.2005.00545.x. PubMed DOI

Mehta J.M., Chester R.C., Kling J.M. The Timing Hypothesis: Hormone Therapy for Treating Symptomatic Women During Menopause and Its Relationship to Cardiovascular Disease. J. Womens Health. 2019;28:705–711. doi: 10.1089/jwh.2018.7201. PubMed DOI

Stuenkel C.A. Menopause, hormone therapy and diabetes. Climacteric. 2017;20:10–21. doi: 10.1080/13697137.2016.1267723. PubMed DOI

Malínská H., Hüttl M., Miklánková D., Trnovská J., Zapletalová I., Poruba M., Marková I. Ovariectomy-Induced Hepatic Lipid and Cytochrome P450 Dysmetabolism Precedes Serum Dyslipidemia. Int. J. Mol. Sci. 2021;22:4527. doi: 10.3390/ijms22094527. PubMed DOI PMC

Boldarine V.T., Pedroso A.P., Brandão-Teles C., LoTurco E.G., Nascimento C.M.O., Oyama L.M., Bueno A.A., Martins-de-Souza D., Ribeiro E.B. Ovariectomy modifies lipid metabolism of retroperitoneal white fat in rats: A proteomic aproach. Am. J. Physiol. Endocrinol. Metab. 2020;319:E427–E437. doi: 10.1152/ajpendo.00094.2020. PubMed DOI

Vrána A., Kazdová L. The hereditary hypertriglyceridemic nonobese rat: An experimental model of human hypertriglyceridemia. Transplant. Proc. 1990;22:2579. PubMed

Zicha J., Pechánová O., Cacányiová S., Cebová M., Kristek F., Török J., Simko F., Dobesová Z., Kunes J. Hereditary hypertriglyceridemic rat: A suitable model of cardiovascular disease and metabolic syndrome? Physiol. Res. 2006;55((Suppl. 1)):S49–S63. doi: 10.33549/physiolres.930000.55.S1.49. PubMed DOI

Malinska H., Huttl M., Oliyarnyk O., Markova I., Poruba M., Racova Z., Kazdova L., Vecera R. Beneficial effects of troxerutin on metabolic disorders in non-obese model of metabolic syndrome. PLoS ONE. 2019;14:e0220377. doi: 10.1371/journal.pone.0220377. PubMed DOI PMC

Amengual-Cladera E., Capllonch-Amer G., Lladó I., Gianotti M., Proenza A.M. Proteomic study of periovarian tissue in 17β-estradiol-treated and untreated ovariectomized rats. Biochem. Cell Biol. 2016;94:167–175. doi: 10.1139/bcb-2015-0077. PubMed DOI

Després J.-P., Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444:881–887. doi: 10.1038/nature05488. PubMed DOI

Qi N., Kazdova L., Zidek V., Landa V., Kren V., Pershadsingha H.A., Lezin E.S., Abumrad N.A., Pravenec M., Kurtz T.W. Pharmacogenetic evidence that cd36 is a key determinant of the metabolic effects of pioglitazone. J. Biol. Chem. 2002;277:48501–48507. doi: 10.1074/jbc.M206655200. PubMed DOI

Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.J. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 1951;193:265–275. doi: 10.1016/S0021-9258(19)52451-6. PubMed DOI

Kuleshov M.V., Jones M.R., Rouillard A.D., Fernandez N.F., Duan Q., Wang Z., Koplev S., Jenkins S.L., Jagodnik K.M., Lachmann A., et al. Enrichr: A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:W90–W97. doi: 10.1093/nar/gkw377. PubMed DOI PMC

Benjamin E.J., Muntner P., Alonso A., Bittencourt M.S., Callaway C.W., Carson A.P., Chamberlain A.M., Chang A.R., Cheng S., Das S.R. Heart disease and stroke statistics-2019 update: A report from the American Heart Association. Circulation. 2019;139:e506–e532. doi: 10.1161/CIR.0000000000000659. PubMed DOI

Sites C.K., Brochu M., Tchernov A., Poehlman E.T. Relationship between hormone replacement therapy use with body fat distribution and insulin sensitivity in obese postmenopausal women. Metabolism. 2001;50:835–840. doi: 10.1053/meta.2001.24878. PubMed DOI

Kim J.H., Cho H.T., Kim Y.J. The role of estrogen in adipose tissue metabolism: Insights into glucose homeostasis regulation. Endocr. J. 2014;61:1055–1067. doi: 10.1507/endocrj.EJ14-0262. PubMed DOI

Wu S.I., Chou P., Tsai S.T. The impact of years since menopause on the development of impaired glucose tolerance. J. Clin. Epidemiol. 2001;54:117–120. doi: 10.1016/S0895-4356(00)00284-5. PubMed DOI

Kumagai S., Holmäng A., Björntorp P. The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol. Scand. 1993;149:91–97. doi: 10.1111/j.1748-1716.1993.tb09596.x. PubMed DOI

Kanaya A.M., Herrington D., Vittinghoff E., Lin F., Grady D., Bittner V., Cauley J.A., Barrett-Connor E. Glycemic effects of postmenopausal hormone therapy: The heart and estrogen/progestin replacement study: A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 2003;138:1–9. doi: 10.7326/0003-4819-138-1-200301070-00005. PubMed DOI

Mauvais-Jarvis F. Menopause, estrogens and glucose homeostasis in women. Adv. Exp. Med. Biol. 2017;1043:217–225. PubMed

Kim J.H., Meyers M.S., Khuder S.S., Abdallah S.L., Muturi H.T., Russo L., Tate C.R., Hevener A.L., Najjar S.M., Leloup C., et al. Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. Mol. Metab. 2014;3:177–190. doi: 10.1016/j.molmet.2013.12.009. PubMed DOI PMC

Torosyan N., Visrodia P., Torbati T., Minissian M.B., Schufelt C.L. Dyslipidemia in midlife women: Approach and considerations during the postmenopausal transition. Maturitas. 2022;166:14–20. doi: 10.1016/j.maturitas.2022.08.001. PubMed DOI

Liu M.L., Xu X., Rang W.Q., Li Y.J., Song H.P. Influence of ovariectomy and 17β-estradiol treatment on insulin sensitivity, lipid metabolism and post-ischemic cardiac function. Int. J. Cardiol. 2004;97:485–493. doi: 10.1016/j.ijcard.2003.11.046. PubMed DOI

Babei P., Mehdizadeh R., Ansar M.M., Damirchi A. Effects of ovariectomy and estrogen replacement therapy on visceral adipose tissue and serum adiponectin levels in rats. Menopause Int. 2010;16:100–104. doi: 10.1258/mi.2010.010028. PubMed DOI

Hodis H.N., Mack W.J., Henderson V.W., Shoupe D., Budoff M.J., Hwang-Levine J., Li Y., Feng M., Dustin L., Kono N., et al. Vascular effects of early versus late postmenopausal treatment with estradiol. N. Engl. J. Med. 2016;374:1221–1231. doi: 10.1056/NEJMoa1505241. PubMed DOI PMC

Manson J.E., Hsia J., Johnson K.C., Rossouw J.E., Assaf A.R., Lasser N.L., Trevisan M., Black H.R., Heckbert S.R., Detrano R., et al. Women’s Health Initiative, I. Estrogen plus progestin and the risk of coronary heart disease. N. Engl. J. Med. 2003;349:523–534. doi: 10.1056/NEJMoa030808. PubMed DOI

Hulley S., Grady D., Bush T., Furberg C., Herrington D., Riggs B., Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–613. doi: 10.1001/jama.280.7.605. PubMed DOI

Wiegratz I., Jung-Hoffmann C., Gross W., Kuhl H. Effect of two oral contraceptives containing ethinyl estradiol and gestodene or norgestimate on different lipid and lipoprotein parameters. Contraception. 1998;58:83–91. doi: 10.1016/S0010-7824(98)00074-2. PubMed DOI

Walsh B.W., Shiff I., Rosner B., Greenberg I., Ravnikar V., Sacks F.M. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N. Engl. J. Med. 1991;325:1196–1204. doi: 10.1056/NEJM199110243251702. PubMed DOI

Schaeffer E.J., Foster D.M., Zech L.A., Lindgren F.T., Brewer H.B., Jr., Levy R.I. The effects of estrogen administration on plasma lipoprotein metabolism in premenopausal females. J. Clin. Endocrinol. Metab. 1983;572:262–267. doi: 10.1210/jcem-57-2-262. PubMed DOI

Pitha J., Huttl M., Malinska H., Miklankova D., Bartuskova H., Hlinka T., Markova I. Cardiovascular, metabolic and inflammatory changes after ovariectomy and estradiol substitution in hereditary hypertriglyceridemic rats. Int. J. Mol. Sci. 2022;23:2825. doi: 10.3390/ijms23052825. PubMed DOI PMC

Geisler C.E., Renquist B.J. Hepatic lipid accumulation: Cause and consequence of dysregulated glucoregulatory hormones. J. Endocrinol. 2017;234:R1–R21. doi: 10.1530/JOE-16-0513. PubMed DOI

Rogers N.H., Perfield J.W., Strissel K.J., Obin M.S., Greenberg A.S. Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology. 2009;150:2161–2168. doi: 10.1210/en.2008-1405. PubMed DOI PMC

Schadinger S.E., Bucher L.R., Schreiber B.M., Farmer S.R. PPARγ2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes. Am. J. Physiol. Endocrinol. Metab. 2005;288:E1195–E1205. doi: 10.1152/ajpendo.00513.2004. PubMed DOI

Palmisano B.T., Zhu L., Stafford J.M. Estrogens in the regulation of liver lipid metabolism. Adv. Exp. Med. Biol. 2017;1043:227–256. PubMed PMC

Zhu L., Brown W.C., Cai Q., Krust A., Chambon P., McGuiness O.P., Stafford J.M. Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Diabetes. 2013;62:424–434. doi: 10.2337/db11-1718. PubMed DOI PMC

Hevener A.L., Clegg D.J., Mauvais-Jarvis F. Impaired estrogen receptor action in the pathogenesis of metabolic syndrome. Pt 3Mol. Cell Endocrinol. 2015;418:306–321. doi: 10.1016/j.mce.2015.05.020. PubMed DOI PMC

Mauvais-Jarvis F. Estrogen and androgen receptors: Regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol. Metab. 2011;22:24–33. doi: 10.1016/j.tem.2010.10.002. PubMed DOI PMC

Markova I., Miklankova D., Hüttl M., Kacer P., Skibova J., Kucera J., Sedlacek R., Kacerova T., Kazdova L., Malinska H. The effect of lipotoxicity on renal dysfunction in a nonobese rat model of metabolic syndrome: A urinary proteomic approach. J. Diabetes Res. 2019;2019:8712979. doi: 10.1155/2019/8712979. PubMed DOI PMC

Rabe K., Lehrke M., Parhofer K.G., Broedl U.C. Adipokines and insulin resistance. Mol. Med. 2008;14:741–751. doi: 10.2119/2008-00058.Rabe. PubMed DOI PMC

Sieminska L., Wojciechowska C., Niedziolka D., Marek B., Kos-Kudla B., Kajdaniuk D., Nowak M. Effect of menopause and hormone replacement therapy on serum adiponectin levels. Metabolism. 2005;54:1610–1614. doi: 10.1016/j.metabol.2005.06.008. PubMed DOI

Mankowska A., Nowak L., Sypniewska G. Adiponectin and metabolic syndrome in women at menopause. EJIFCC. 2009;19:173–184. PubMed PMC

Lu J.Y., Huang K.C., Chang L.C., Huang Y.S., Chi Y.C., Su T.C., Cheng C.L., Yang W.S. Adiponectin: A biomarker of obesity-induced insulin resistance in adipose tissue and beyond. J. Biomed. Sci. 2008;15:565–576. doi: 10.1007/s11373-008-9261-z. PubMed DOI

Vieira Potter V.J., Strissel K.J., Xie C., Chang E., Bennet G., Defuria J., Obin M.S., Greenberg A.S. Adipose tissue inflammation and reduced insulin sensitivity in ovariectomized mice occurs in the absence of increased adiposity. Endocrinology. 2012;159:4266–4277. doi: 10.1210/en.2011-2006. PubMed DOI PMC

Lv Y., Zhang S., Weng X., Huang J., Zhao H., Dai X., Bai X., Bao X., Zhao C., Zeng M., et al. Estrogen deficiency accelerates postmenopausal atherosclerosis by inducing endothelial cell ferroptosis through inhibiting NRF2/GPX4 pathway. FASEB J. 2023;37:e22992. doi: 10.1096/fj.202300083R. PubMed DOI

Pope L.E. Dixon SJ. Regulation of ferroptosis by lipid metabolism. Trends Cell Biol. 2023;33:1077–1087. doi: 10.1016/j.tcb.2023.05.003. PubMed DOI PMC

Lehr S., Hartwig S., Lamers D., Famulla S., Müller S., Hanisch F.G., Cuvelier C., Ruige J., Eckhardt K., Ouwens D.M., et al. Identification and validation of novel adipokines released from primary human adipocytes. Mol. Cell Proteomics. 2012;11:M111.010504. doi: 10.1074/mcp.M111.010504. PubMed DOI PMC

Sárvári A.K., Van Hauwaert E.L., Markussen L.K., Gammelmark E., Marcher A.B., Ebbesen M.F., Nielsen R., Brewer J.R., Madsen J.G.S., Mandrup S. Plasticity of Epididymal Adipose Tissue in Response to Diet-Induced Obesity at Single-Nucleus Resolution. Cell Metab. 2021;33:437–453.e5. doi: 10.1016/j.cmet.2020.12.004. PubMed DOI

Lundholm L., Movérare S., Steffensen K.R., Nilsson M., Otsuki M., Ohlsson C., Gustafsson J.A., Dahlman-Wright K. Gene expression profiling identifies liver X receptor alpha as an estrogen-regulated gene in mouse adipose tissue. J. Mol. Endocrinol. 2004;32:879–892. doi: 10.1677/jme.0.0320879. PubMed DOI

Ye P., Yoshioka M., Gan L., St-Amand J. Regulation of global gene expression by ovariectomy and estrogen in female adipose tissue. Obes. Res. 2005;13:1024–1030. doi: 10.1038/oby.2005.120. PubMed DOI

Belkaid A., Duguay S.R., Ouellette R.J., Surette M.E. 17β-estradiol induces stearoyl-CoA desaturase-1 expression in estrogen receptor-positive breast cancer cells. BMC Cancer. 2015;15:440. doi: 10.1186/s12885-015-1452-1. PubMed DOI PMC

Cohen P., Miyazaki M., Socci N.D., Hagge-Greenberg A., Liedtke W., Soukas A.A., Sharma R., Hudgins L.C., Ntambi J.M., Friedman J.M. Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science. 2002;297:240–243. doi: 10.1126/science.1071527. PubMed DOI

Sun Q., Xing X., Wang H., Wan K., Fan R., Liu C., Wang Y., Wu W., Wang Y., Wang R. SCD1 is the critical signaling hub to mediate metabolic diseases: Mechanism and the development of its inhibitors. Biomed. Pharmacother. 2023;170:115586. doi: 10.1016/j.biopha.2023.115586. PubMed DOI

Naser W., Maymand S., Rivera L.R., Connor T., Liongue C., Smith C.M., Aston-Mourney K., McCulloch D.R., McGee A.L., Ward A.C. Cytokine-inducible SH2 domain containing protein contributes to regulation of adiposity, food intake, and glucose metabolism. FASEB J. 2022;36:e22320. doi: 10.1096/fj.202101882R. PubMed DOI

Xiao F., Deng J., Jiao F., Hu X., Jiang H., Yuan F., Chen S., Niu Y., Jiang X., Guo F. Hepatic cytokine-inducible SH2-containing protein (CISH) regulates gluconeogenesis via cAMP-responsive element binding protein (CREB) FASEB J. 2022;36:e22541. doi: 10.1096/fj.202200870R. PubMed DOI