vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-22-20vavilov-3292Research ArticleРЕПРОДУКТИВНЫЕ ТЕХНОЛОГИИPHYSIOLOGICAL GENETICSЗависимые и независимые от уровня эстрадиола эффекты FGF21 у самок мышей с ожирениемEstradiol-dependent and independent effects of FGF21 in obese female micehttps://orcid.org/0000-0001-7628-5856ЯковлеваТ. В.JakovlevaT. V.

Новосибирск

Novosibirsk

tatyanajakovleva@yandex.ruhttps://orcid.org/0000-0003-4192-2020КазанцеваА. Ю.KazantsevaA. Yu.

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Novosibirsk

https://orcid.org/0000-0003-3907-3488ДубининаА. Д.DubininaA. D.

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Novosibirsk

https://orcid.org/0000-0001-7168-1438БалыбинаН. Ю.BalybinaN. Yu.

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Novosibirsk

https://orcid.org/0000-0002-4029-6518БарановК. О.BaranovK. O.

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Novosibirsk

https://orcid.org/0000-0002-6417-9893МакароваE. Н.MakarovaE. N.

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Novosibirsk

https://orcid.org/0000-0002-7246-4758БажанН. М.BazhanN. M.

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Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationИнститут молекулярной и клеточной биологии Сибирского отделения Российской академии наукРоссияInstitute of Molecular and Cellular Biology of the Siberian Branch of the Russian Academy of SciencesRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian Federation202204042022262159168Copyright © Яковлева Т.В., Казанцева А.Ю., Дубинина А.Д., Балыбина Н.Ю., Баранов К.О., Макарова E.Н., Бажан Н.М., 20222022Яковлева Т.В., Казанцева А.Ю., Дубинина А.Д., Балыбина Н.Ю., Баранов К.О., Макарова E.Н., Бажан Н.М.Jakovleva T.V., Kazantseva A.Y., Dubinina A.D., Balybina N.Y., Baranov K.O., Makarova E.N., Bazhan N.M.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3292

Синтезируемый в печени фактор роста фибробластов 21 (FGF21), действуя как гормон, повышает чувствительность к инсулину и расход энергии. Введение FGF21 оказывает мощное благотворное воздействие у людей, обезьян и грызунов с ожирением и диабетом второго типа. Терапевтические эффекты FGF21 исследованы главным образом на самцах, они не всегда проявляются у самок и сопровождаются поло-специфической активацией экспрессии генов в тканях. Мы предположили, что одной из причин полового диморфизма в ответе на FGF21 является действие эстрадиола (Е2). В настоящее время неизвестно, как эстрадиол влияет на проявление фармакологических эффектов FGF21. Задачей данного исследования было изучение влияния FGF21 на метаболические характеристики, потребление пищи и экспрессию генов углеводного и жирового обмена в печени, жировой ткани и гипоталамусе у самок мышей с алиментарным ожирением на фоне низкого (овариэктомия) и высокого (овариэктомия + Е2) уровня эстрадиола в крови. У овариэктомированных самок развитие ожирения индуцировали потреблением сладко-жирной диеты (стандартный корм, сало, печенье) в течение 8 недель. Мы оценили эффекты FGF21 на массу тела, показатели крови, выбор компонентов диеты, экспрессию генов в тканях при раздельном и совместном введении с Е2 в течение 13 дней. У овариэктомированных самок с ожирением FGF21, независимо от введения Е2, не влиял на массу тела и жировой ткани, толерантность к глюкозе, повышал потребление стандартного корма, снижал уровень глюкозы в крови, подавлял в печени собственную экспрессию (Fgf21), а также экспрессию генов G6pc и Acacα. Впервые показано влияние эстрадиола на эффекты FGF21: ингибирование FGF21-влияния на экспрессию Irs2 и Pklr в печени и потенцирование FGF21-стимулированной экспрессии Lepr и Klb в гипоталамусе. Кроме того, на фоне введения эстрадиола не проявлялось ингибирующее влияние FGF21 на уровень инсулина в крови, а в подкожной белой жировой ткани проявлялось ингибирующее влияние FGF21 на экспрессию Cpt1α и не проявлялось активирующее влияние FGF21 на экспрессию генов Insr и Acacβ. Полученные данные позволяют заключить, что у овариэктомированных самок с ожирением отсутствие эффектов FGF21 на массу тела и жировой ткани и его благотворное влияние на потребление пищи и уровень глюкозы в крови не связаны с действием эстрадиола. Однако эстрадиол влияет на транскрипционные эффекты FGF21 в печени, белом жире и гипоталамусе, что может лежать в основе половых различий в его действии на экспрессию метаболических генов и, возможно, половых различий его фармакологических эффектов.

The f ibroblast growth factor 21 (FGF21) synthesized in the liver, acting as a hormone, increases insulin sensitivity and energy expenditure. FGF21 administration has potent benef icial effects on obesity and diabetes in humans, cynomolgus monkey, and rodents. The therapeutic effects of FGF21 have been studied mainly in males. They are not always manifested in females, and they are accompanied by sex-specif ic activation of gene expression in tissues. We have suggested that one of the causes of sexual dimorphism in response to FGF21 is the effect of estradiol (E2). Currently, it is not known how estradiol modif ies the pharmacological effects of FGF21. The objective of this study was to study the inf luence of FGF21 on metabolic characteristics, food intake, and the expression of carbohydrate and fat metabolism genes in the liver, adipose tissue, and hypothalamus in female mice with alimentary obesity and low (ovariectomy) or high (ovariectomy + E2) blood estradiol level. In ovariectomized (OVX) females, the development of obesity was induced by the consumption of a high sweet-fat diet (standard chow, lard, and cookies) for 8 weeks. We investigated the effects of FGF21 on body weight, blood levels, food preferences and gene expression in tissues when FGF21 was administered separately or in combination with E2 for 13 days. In OVX obese females, FGF21, regardless of E2-treatment, did not affect body weight, and adipose tissue weight, or glucose tolerance but increased the consumption of standard chow, reduced blood glucose levels, and suppressed its own expression in the liver (Fgf21), as well as the expression of the G6pc and Acacα genes. This study is the f irst to show the modif ication of FGF21 effects by estradiol: inhibition of FGF21-inf luence on the expression of Irs2 and Pklr in the liver and potentiation of the FGF21-stimulated expression of Lepr and Klb in the hypothalamus. In addition, when administered together with estradiol, FGF21 exerted an inhibitory effect on the expression of Cpt1α in subcutaneous white adipose tissue (scWAT), whereas no stimulating FGF21 effects on the expression of Insr and Acacβ in scWAT or inhibitory FGF21 effect on the plasma insulin level were observed. The results suggest that the absence of FGF21 effects on body and adipose tissue weights in OVX obese females and its benef icial effect on food intake and blood glucose levels are not associated with the action of estradiol. However, estradiol affects the transcriptional effects of FGF21 in the liver, white adipose tissue, and hypothalamus, which may underlie sex differences in the FGF21 effect on the expression of metabolic genes and, possibly, in pharmacological FGF21 effects.

FGF21эстрадиолпеченьжировая тканьпищевое предпочтениеэкспрессия геновполовые различияFGF21estradiolliveradipose tissuefood preferencegene expressionsex differencesThis work was supported by the Russian Science Foundation, project 17-15-01036-П. The use of the equipment of the Department of Experimental Animal Genetic Resources, ICG, was supported by the Russian Ministry of Education and Science, project RFMEFI62117X0015.ReferencesAllard C., Bonnet F., Xu B., Coons L., Albarado D., Hill C., Fagherazzi G., Korach K.S., Levin E.R., Lefante J., Morrison C., MauvaisJarvis F. Activation of hepatic estrogen receptor-α increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice. Mol. Metab. 2019;22:62-70. DOI 10.1016/j.molmet.2019.02.002.Allard C., Bonnet F., Xu B., Coons L., Albarado D., Hill C., Fagherazzi G., Korach K.S., Levin E.R., Lefante J., Morrison C., MauvaisJarvis F. Activation of hepatic estrogen receptor-α increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice. Mol. Metab. 2019;22:62-70. DOI 10.1016/j.molmet.2019.02.002.Bazhan N., Yakovleva T., Denisova E., Dubinina A., Makarova E. Antidiabetic FGF21 action depended on sex and exerted only in male mice with diet induced obesity. Obes. Facts. 2019; 12(Suppl.1):189. DOI 10.1159/000489691.Bazhan N., Yakovleva T., Denisova E., Dubinina A., Makarova E. Antidiabetic FGF21 action depended on sex and exerted only in male mice with diet induced obesity. Obes. Facts. 2019; 12(Suppl.1):189. DOI 10.1159/000489691.Berglund E.D., Vianna C.R., Donato J., Jr., Kim M.H., Chuang J.C., Lee C.E., Lauzon D.A., Lin P., Brule L.J., Scott M.M., Coppari R., Elmquist J.K. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J. Clin. Invest. 2012;122(3):1000-1009. DOI 10.1172/JCI59816.Berglund E.D., Vianna C.R., Donato J., Jr., Kim M.H., Chuang J.C., Lee C.E., Lauzon D.A., Lin P., Brule L.J., Scott M.M., Coppari R., Elmquist J.K. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J. Clin. Invest. 2012;122(3):1000-1009. DOI 10.1172/JCI59816.Bian C., Bai B., Gao Q., Li S., Zhao Y. 17β-estradiol regulates glucose metabolism and insulin secretion in rat islet β cells through GPER and Akt/mTOR/GLUT2 pathway. Front. Endocrinol. (Lausanne). 2019;10:531. DOI 10.3389/fendo.2019.00531.Bian C., Bai B., Gao Q., Li S., Zhao Y. 17β-estradiol regulates glucose metabolism and insulin secretion in rat islet β cells through GPER and Akt/mTOR/GLUT2 pathway. Front. Endocrinol. (Lausanne). 2019;10:531. DOI 10.3389/fendo.2019.00531.BonDurant L.D., Potthoff M.J. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu. Rev. Nutr. 2018;38: 173-196. DOI 10.1146/annurev-nutr-071816-064800.BonDurant L.D., Potthoff M.J. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu. Rev. Nutr. 2018;38: 173-196. DOI 10.1146/annurev-nutr-071816-064800.Chau M.D., Gao J., Yang Q., Wu Z., Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPKSIRT1-PGC-1α pathway. Proc. Natl. Acad. Sci. USA. 2010; 107(28):12553-12558. DOI 10.1073/pnas.1006962107.Chau M.D., Gao J., Yang Q., Wu Z., Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPKSIRT1-PGC-1α pathway. Proc. Natl. Acad. Sci. USA. 2010; 107(28):12553-12558. DOI 10.1073/pnas.1006962107.Coskun T., Bina H.A., Schneider M.A., Dunbar J.D., Hu C.C., Chen Y., Moller D.E., Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008;149(12):6018-6027. DOI 10.1210/en.2008-0816.Coskun T., Bina H.A., Schneider M.A., Dunbar J.D., Hu C.C., Chen Y., Moller D.E., Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology. 2008;149(12):6018-6027. DOI 10.1210/en.2008-0816.Cowley M.A., Smart J.L., Rubinstein M., Cerdán M.G., Diano S., Horvath T.L., Cone R.D., Low M.J. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411(6836):480-484. DOI 10.1038/35078085.Cowley M.A., Smart J.L., Rubinstein M., Cerdán M.G., Diano S., Horvath T.L., Cone R.D., Low M.J. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature. 2001;411(6836):480-484. DOI 10.1038/35078085.Fisher F.M., Estall J.L., Adams A.C., Antonellis P.J., Bina H.A., Flier J.S., Kharitonenkov A., Spiegelman B.M., Maratos-Flier E. Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo. Endocrinology. 2011;152(8):2996-3004. DOI 10.1210/en.2011-0281.Fisher F.M., Estall J.L., Adams A.C., Antonellis P.J., Bina H.A., Flier J.S., Kharitonenkov A., Spiegelman B.M., Maratos-Flier E. Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo. Endocrinology. 2011;152(8):2996-3004. DOI 10.1210/en.2011-0281.Fisher F.M., Maratos-Flier E. Understanding the physiology of FGF21. Annu. Rev. Physiol. 2016;78:223-241. DOI 10.1146/annurevphysiol-021115-105339.Fisher F.M., Maratos-Flier E. Understanding the physiology of FGF21. Annu. Rev. Physiol. 2016;78:223-241. DOI 10.1146/annurevphysiol-021115-105339.Gao H., Bryzgalova G., Hedman E., Khan A., Efendic S., Gustafsson J.A., Dahlman-Wright K. Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol. Endocrinol. 2006;20(6):1287-1299. DOI 10.1210/me.2006-0012.Gao H., Bryzgalova G., Hedman E., Khan A., Efendic S., Gustafsson J.A., Dahlman-Wright K. Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol. Endocrinol. 2006;20(6):1287-1299. DOI 10.1210/me.2006-0012.Hill C.M., Laeger T., Dehner M., Albarado D.C., Clarke B., Wanders D., Burke S.J., Collier J.J., Qualls-Creekmore E., Solon-Biet S.M., Simpson S.J., Berthoud H.R., Münzberg H., Morrison C.D. FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism. Cell Rep. 2019;27(10): 2934-2947.e3. DOI 10.1016/j.celrep.2019.05.022.Hill C.M., Laeger T., Dehner M., Albarado D.C., Clarke B., Wanders D., Burke S.J., Collier J.J., Qualls-Creekmore E., Solon-Biet S.M., Simpson S.J., Berthoud H.R., Münzberg H., Morrison C.D. FGF21 signals protein status to the brain and adaptively regulates food choice and metabolism. Cell Rep. 2019;27(10): 2934-2947.e3. DOI 10.1016/j.celrep.2019.05.022.Hua L., Zhuo Y., Jiang D., Li J., Huang X., Zhu Y., Li Z., Yan L., Jin C., Jiang X., Che L., Fang Z., Lin Y., Xu S., Li J., Feng B., Wu D. Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning. FASEB J. 2018;32(10):5602-5611. DOI 10.1096/fj.201800240R.Hua L., Zhuo Y., Jiang D., Li J., Huang X., Zhu Y., Li Z., Yan L., Jin C., Jiang X., Che L., Fang Z., Lin Y., Xu S., Li J., Feng B., Wu D. Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning. FASEB J. 2018;32(10):5602-5611. DOI 10.1096/fj.201800240R.Kharitonenkov A., Shiyanova T.L., Koester A., Ford A.M., Micanovic R., Galbreath E.J., Sandusky G.E., Hammond L.J., Moyers J.S., Owens R.A., Gromada J., Brozinick J.T., Hawkins E.D., Wroblewski V.J., Li D.S., Mehrbod F., Jaskunas S.R., Shanafelt A.B. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 2005;115(6):1627-1635. DOI 10.1172/JCI23606.Kharitonenkov A., Shiyanova T.L., Koester A., Ford A.M., Micanovic R., Galbreath E.J., Sandusky G.E., Hammond L.J., Moyers J.S., Owens R.A., Gromada J., Brozinick J.T., Hawkins E.D., Wroblewski V.J., Li D.S., Mehrbod F., Jaskunas S.R., Shanafelt A.B. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 2005;115(6):1627-1635. DOI 10.1172/JCI23606.Kurosu H., Choi M., Ogawa Y., Dickson A.S., Goetz R., Eliseenkova A.V., Mohammadi M., Rosenblatt K.P., Kliewer S.A., Kuro- O M. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 2007;282(37):26687-26695. DOI 10.1074/jbc.M704165200.Kurosu H., Choi M., Ogawa Y., Dickson A.S., Goetz R., Eliseenkova A.V., Mohammadi M., Rosenblatt K.P., Kliewer S.A., Kuro- O M. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 2007;282(37):26687-26695. DOI 10.1074/jbc.M704165200.Larson K.R., Chaffin A.T., Goodson M.L., Fang Y., Ryan K.K. Fibroblast growth factor-21 controls dietary protein intake in male mice. Endocrinology. 2019;160(5):1069-1080. DOI 10.1210/en.2018-01056.Larson K.R., Chaffin A.T., Goodson M.L., Fang Y., Ryan K.K. Fibroblast growth factor-21 controls dietary protein intake in male mice. Endocrinology. 2019;160(5):1069-1080. DOI 10.1210/en.2018-01056.Makarova E., Kazantseva A., Dubinina A., Jakovleva T., Balybina N., Baranov K., Bazhan N. The same metabolic response to FGF21 administration in male and female obese mice is accompanied by sex-specific changes in adipose tissue gene expression. Int. J. Mol. Sci. 2021;22(19):10561. DOI 10.3390/ijms221910561.Makarova E., Kazantseva A., Dubinina A., Jakovleva T., Balybina N., Baranov K., Bazhan N. The same metabolic response to FGF21 administration in male and female obese mice is accompanied by sex-specific changes in adipose tissue gene expression. Int. J. Mol. Sci. 2021;22(19):10561. DOI 10.3390/ijms221910561.Makarova E.N., Yakovleva T.V., Balyibina N.Y., Baranov K.O., Denisova E.I., Dubinina A.D., Feofanova N.A., Bazhan N.M. Pharmacological effects of fibroblast growth factor 21 are sexspecific in mice with the lethal yellow (Ay) mutation. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2020;24(2):200-208. DOI 10.18699/VJ20.40-o.Makarova E.N., Yakovleva T.V., Balyibina N.Y., Baranov K.O., Denisova E.I., Dubinina A.D., Feofanova N.A., Bazhan N.M. Pharmacological effects of fibroblast growth factor 21 are sexspecific in mice with the lethal yellow (Ay) mutation. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2020;24(2):200-208. DOI 10.18699/VJ20.40-o.Nadal A., Alonso-Magdalena P., Soriano S., Ropero A.B., Quesada I. The role of oestrogens in the adaptation of islets to insulin resistance. J. Physiol. 2009;587(Pt.21):5031-5037. DOI 10.1113/jphysiol.2009.177188.Nadal A., Alonso-Magdalena P., Soriano S., Ropero A.B., Quesada I. The role of oestrogens in the adaptation of islets to insulin resistance. J. Physiol. 2009;587(Pt.21):5031-5037. DOI 10.1113/jphysiol.2009.177188.Owen B.M., Mangelsdorf D.J., Kliewer S.A. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol. Metab. 2015;26(1):22-29. DOI 10.1016/j.tem.2014.10.002.Owen B.M., Mangelsdorf D.J., Kliewer S.A. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol. Metab. 2015;26(1):22-29. DOI 10.1016/j.tem.2014.10.002.Palmisano B.T., Zhu L., Stafford J.M. Role of estrogens in the regulation of liver lipid metabolism. Adv. Exp. Med. Biol. 2017;1043: 227-256. DOI 10.1007/978-3-319-70178-3_12.Palmisano B.T., Zhu L., Stafford J.M. Role of estrogens in the regulation of liver lipid metabolism. Adv. Exp. Med. Biol. 2017;1043: 227-256. DOI 10.1007/978-3-319-70178-3_12.Pan Y., Wang B., Zheng J., Xiong R., Fan Z., Ye Y., Zhang S., Li Q., Gong F., Wu C., Lin Z., Li X., Pan X. Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling-dependent manner. J. Cell. Mol. Med. 2019;23(2):1059-1071. DOI 10.1111/jcmm.14007.Pan Y., Wang B., Zheng J., Xiong R., Fan Z., Ye Y., Zhang S., Li Q., Gong F., Wu C., Lin Z., Li X., Pan X. Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling-dependent manner. J. Cell. Mol. Med. 2019;23(2):1059-1071. DOI 10.1111/jcmm.14007.Riant E., Waget A., Cogo H., Arnal J.F., Burcelin R., Gourdy P. Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology. 2009;150(5): 2109-2117. DOI 10.1210/en.2008-0971.Riant E., Waget A., Cogo H., Arnal J.F., Burcelin R., Gourdy P. Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology. 2009;150(5): 2109-2117. DOI 10.1210/en.2008-0971.Talukdar S., Zhou Y., Li D., Rossulek M., Dong J., Somayaji V., Weng Y., Clark R., Lanba A., Owen B.M., Brenner M.B., Trimmer J.K., Gropp K.E., Chabot J.R., Erion D.M., Rolph T.P., Goodwin B., Calle R.A. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 2016;23(3): 427-440. DOI 10.1016/j.cmet.2016.02.001.Talukdar S., Zhou Y., Li D., Rossulek M., Dong J., Somayaji V., Weng Y., Clark R., Lanba A., Owen B.M., Brenner M.B., Trimmer J.K., Gropp K.E., Chabot J.R., Erion D.M., Rolph T.P., Goodwin B., Calle R.A. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 2016;23(3): 427-440. DOI 10.1016/j.cmet.2016.02.001.Thammacharoen S., Geary N., Lutz T.A., Ogawa S., Asarian L. Divergent effects of estradiol and the estrogen receptor-α agonist PPT on eating and activation of PVN CRH neurons in ovariectomized rats and mice. Brain Res. 2009;1268:88-96. DOI 10.1016/j.brainres.2009.02.067.Thammacharoen S., Geary N., Lutz T.A., Ogawa S., Asarian L. Divergent effects of estradiol and the estrogen receptor-α agonist PPT on eating and activation of PVN CRH neurons in ovariectomized rats and mice. Brain Res. 2009;1268:88-96. DOI 10.1016/j.brainres.2009.02.067.Véniant M.M., Komorowski R., Chen P., Stanislaus S., Winters K., Hager T., Zhou L., Wada R., Hecht R., Xu J. Long-acting FGF21 has enhanced efficacy in diet-induced obese mice and in obese rhesus monkeys. Endocrinology. 2012;153(9):4192-4203. DOI 10.1210/en.2012-1211.Véniant M.M., Komorowski R., Chen P., Stanislaus S., Winters K., Hager T., Zhou L., Wada R., Hecht R., Xu J. Long-acting FGF21 has enhanced efficacy in diet-induced obese mice and in obese rhesus monkeys. Endocrinology. 2012;153(9):4192-4203. DOI 10.1210/en.2012-1211.Vrtačnik P., Ostanek B., Mencej-Bedrač S., Marc J. The many faces of estrogen signaling. Biochem. Med. (Zagreb). 2014;24(3):329-342. DOI 10.11613/BM.2014.035.Vrtačnik P., Ostanek B., Mencej-Bedrač S., Marc J. The many faces of estrogen signaling. Biochem. Med. (Zagreb). 2014;24(3):329-342. DOI 10.11613/BM.2014.035.Xu J., Stanislaus S., Chinookoswong N., Lau Y.Y., Hager T., Patel J., Ge H., Weiszmann J., Lu S.C., Graham M., Busby J., Hecht R., Li Y.S., Li Y., Lindberg R., Véniant M.M. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models – association with liver and adipose tissue effects. Am. J. Physiol. Endocrinol. Metab. 2009;297(5):E1105-E1114. DOI 10.1152/ajpendo.00348.2009.Xu J., Stanislaus S., Chinookoswong N., Lau Y.Y., Hager T., Patel J., Ge H., Weiszmann J., Lu S.C., Graham M., Busby J., Hecht R., Li Y.S., Li Y., Lindberg R., Véniant M.M. Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models – association with liver and adipose tissue effects. Am. J. Physiol. Endocrinol. Metab. 2009;297(5):E1105-E1114. DOI 10.1152/ajpendo.00348.2009.Yan H., Yang W., Zhou F., Li X., Pan Q., Shen Z., Han G., Newell-Fugate A., Tian Y., Majeti R., Liu W., Xu Y., Wu C., Allred K., Allred C., Sun Y., Guo S. Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor Foxo1. Diabetes. 2019;68(2):291-304. DOI 10.2337/db18-0638.Yan H., Yang W., Zhou F., Li X., Pan Q., Shen Z., Han G., Newell-Fugate A., Tian Y., Majeti R., Liu W., Xu Y., Wu C., Allred K., Allred C., Sun Y., Guo S. Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor Foxo1. Diabetes. 2019;68(2):291-304. DOI 10.2337/db18-0638.

The authors declare that there are no conflicts of interest present.