{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:20:32Z","timestamp":1792113632999,"version":"4.4.0"},"reference-count":80,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T00:00:00Z","timestamp":1638835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["17-15-01036"],"award-info":[{"award-number":["17-15-01036"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the Ay mutation that evokes melanocortin receptor 4 blockade, obesity, and hepatosteatosis. This suggests that the ability of FGF21 to correct melanocortin obesity may depend on sex. This study compares FGF21 action on food intake, locomotor activity, gene expression, metabolic characteristics, and liver state in obese Ay males and females. Ay mice were administered FGF21 for seven days, and metabolic parameters and gene expression in different tissues were assessed. Placebo-treated females were more obese than males and had lower levels of blood insulin and liver triglycerides, and higher expression of genes for insulin signaling in the liver, white adipose tissue (WAT) and muscles, and pro-inflammatory cytokines in the liver. FGF21 administration did not affect body weight, and increased food intake, locomotor activity, expression of Fgf21 and Ucp1 in brown fat and genes related to lipolysis and insulin action in WAT regardless of sex; however, it decreased hyperinsulinemia and hepatic lipid accumulation and increased muscle expression of Cpt1 and Irs1 only in males. Thus, FGF21\u2019s beneficial effects on metabolic disorders associated with melanocortin obesity are more pronounced in males.<\/jats:p>","DOI":"10.3390\/cells10123440","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T09:52:29Z","timestamp":1638870749000},"page":"3440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Fibroblast Growth Factor 21 (FGF21) Administration Sex-Specifically Affects Blood Insulin Levels and Liver Steatosis in Obese Ay Mice"],"prefix":"10.3390","volume":"10","author":[{"given":"Elena","family":"Makarova","sequence":"first","affiliation":[{"name":"The Laboratory of Physiological Genetics, The Institute of Cytology and Genetics, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonina","family":"Kazantseva","sequence":"additional","affiliation":[{"name":"The Laboratory of Physiological Genetics, The Institute of Cytology and Genetics, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3907-3488","authenticated-orcid":false,"given":"Anastasia","family":"Dubinina","sequence":"additional","affiliation":[{"name":"The Laboratory of Physiological Genetics, The Institute of Cytology and Genetics, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Denisova","sequence":"additional","affiliation":[{"name":"The Laboratory of Physiological Genetics, The Institute of Cytology and Genetics, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Jakovleva","sequence":"additional","affiliation":[{"name":"The Laboratory of Physiological Genetics, The Institute of Cytology and Genetics, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Balybina","sequence":"additional","affiliation":[{"name":"The Laboratory of Physiological Genetics, The Institute of Cytology and Genetics, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataliya","family":"Bgatova","sequence":"additional","affiliation":[{"name":"The Laboratory of Physiological Genetics, The Institute of Cytology and Genetics, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4029-6518","authenticated-orcid":false,"given":"Konstantin","family":"Baranov","sequence":"additional","affiliation":[{"name":"The Institute of Molecular and Cellular Biology, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7246-4758","authenticated-orcid":false,"given":"Nadezhda","family":"Bazhan","sequence":"additional","affiliation":[{"name":"The Laboratory of Physiological Genetics, The Institute of Cytology and Genetics, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101152","DOI":"10.1016\/j.molmet.2020.101152","article-title":"FGF19 and FGF21: In NASH we trust","volume":"46","author":"Talukdar","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/s42255-021-00354-2","article-title":"Metabolic Messengers: FGF21","volume":"3","author":"Flippo","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Garza, \u00da., Torres-Oteros, D., Yarritu-Gallego, A., Marrero, P.F., Haro, D., and Relat, J. (2019). Fibroblast Growth Factor 21 and the Adaptive Response to Nutritional Challenges. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194692"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.tem.2019.05.007","article-title":"Going Back to the Biology of FGF21: New Insights","volume":"30","author":"Lewis","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.tips.2019.12.005","article-title":"Targeting FGF21 for the Treatment of Nonalcoholic Steatohepatitis","volume":"41","author":"Zarei","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1172\/JCI23606","article-title":"FGF-21 as a novel metabolic regulator","volume":"115","author":"Kharitonenkov","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6018","DOI":"10.1210\/en.2008-0816","article-title":"Fibroblast Growth Factor 21 Corrects Obesity in Mice","volume":"149","author":"Coskun","year":"2008","journal-title":"Endocrinology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"28992","DOI":"10.1073\/pnas.2012073117","article-title":"Antibody-mediated activation of the FGFR1\/Klotho\u03b2 complex corrects metabolic dysfunction and alters food preference in obese humans","volume":"117","author":"Baruch","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"250","DOI":"10.2337\/db08-0392","article-title":"Fibroblast Growth Factor 21 Reverses Hepatic Steatosis, Increases Energy Expenditure, and Improves Insulin Sensitivity in Diet-Induced Obese Mice","volume":"58","author":"Xu","year":"2008","journal-title":"Diabetes"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1530\/EC-20-0152","article-title":"FGF21 regulates hepatic metabolic pathways to improve steatosis and inflammation","volume":"9","author":"Keinicke","year":"2020","journal-title":"Endocr. Connect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/s41574-020-0386-0","article-title":"The therapeutic potential of FGF21 in metabolic diseases: From bench to clinic","volume":"16","author":"Geng","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1080\/13543784.2020.1718104","article-title":"Fibroblast growth factor (FGF)-21 based therapies: A magic bullet for nonalcoholic fatty liver disease (NAFLD)?","volume":"29","author":"Ritchie","year":"2020","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1016\/j.febslet.2009.09.012","article-title":"Inhibition of lipolysis may contribute to the acute regulation of plasma FFA and glucose by FGF21 in ob\/ob mice","volume":"583","author":"Li","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1210\/en.2010-1262","article-title":"Lack of Overt FGF21 Resistance in Two Mouse Models of Obesity and Insulin Resistance","volume":"153","author":"Hale","year":"2012","journal-title":"Endocrinology"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Weng, Y., Chabot, J.R., Bernardo, B., Yan, Q., Zhu, Y., Brenner, M.B., Vage, C., Logan, A., Calle, R., and Talukdar, S. (2015). Pharmacokinetics (PK), Pharmacodynamics (PD) and Integrated PK\/PD Modeling of a Novel Long Acting FGF21 Clinical Candidate PF-05231023 in Diet-Induced Obese and Leptin-Deficient Obese Mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119104"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3366","DOI":"10.1210\/en.2012-2276","article-title":"Fibroblast Growth Factor 21 Improves Insulin Resistance and Ameliorates Renal Injury in db\/db Mice","volume":"154","author":"Kim","year":"2013","journal-title":"Endocrinology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/s12020-014-0503-8","article-title":"Long-lasting anti-diabetic efficacy of PEGylated FGF-21 and liraglutide in treatment of type 2 diabetic mice","volume":"49","author":"Ye","year":"2015","journal-title":"Endocrine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s12020-015-0801-9","article-title":"Insulin sensitizes FGF21 in glucose and lipid metabolisms via activating common AKT pathway","volume":"52","author":"Yu","year":"2016","journal-title":"Endocrine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.biopha.2016.09.019","article-title":"Efficacy of a combination of high and low dosage of PEGylated FGF-21 in treatment of diabetes in db\/db mice","volume":"84","author":"Xu","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.jdiacomp.2017.01.008","article-title":"Pharmacological efficacy of FGF21 analogue, liraglutide and insulin glargine in treatment of type 2 diabetes","volume":"31","author":"Ye","year":"2017","journal-title":"J. Diabetes Its Complicat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1159\/000487568","article-title":"Liver Plays a Major Role in FGF-21 Mediated Glucose Homeostasis","volume":"45","author":"Liu","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Makarova, E., Kazantseva, A., Dubinina, A., Jakovleva, T., Balybina, N., Baranov, K., and Bazhan, N. (2021). 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., 22.","DOI":"10.3390\/ijms221910561"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1515\/jpem-2020-0129","article-title":"Pharmacological treatment strategies for patients with monogenic obesity","volume":"33","author":"Wiegand","year":"2020","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1056\/NEJMoa022050","article-title":"Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene","volume":"348","author":"Farooqi","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1159\/000450649","article-title":"The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances","volume":"104","author":"Hill","year":"2017","journal-title":"Neuroendocrinology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/nn.4202","article-title":"Melanocortin-4 receptor\u2013regulated energy homeostasis","volume":"19","author":"Krashes","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11892-020-01311-1","article-title":"CNS Regulation of Glucose Homeostasis: Role of the Leptin-Melanocortin System","volume":"20","author":"Hall","year":"2020","journal-title":"Curr. Diabetes Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.1172\/JCI31743","article-title":"The central melanocortin system directly controls peripheral lipid metabolism","volume":"117","author":"Nogueiras","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0092-8674(00)81865-6","article-title":"Targeted Disruption of the Melanocortin-4 Receptor Results in Obesity in Mice","volume":"88","author":"Huszar","year":"1997","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1054\/npep.2002.0890","article-title":"The melanocortin receptors: Lessons from knockout models","volume":"36","author":"Butler","year":"2002","journal-title":"Neuropeptides"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e28118","DOI":"10.7554\/eLife.28118","article-title":"Loss of the melanocortin-4 receptor in mice causes dilated cardiomyopathy","volume":"6","author":"Litt","year":"2017","journal-title":"eLife"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1016\/j.ajpath.2011.07.014","article-title":"Melanocortin 4 Receptor\u2013Deficient Mice as a Novel Mouse Model of Nonalcoholic Steatohepatitis","volume":"179","author":"Itoh","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1172\/JCI46044","article-title":"Genetic approaches to understanding human obesity","volume":"121","author":"Ramachandrappa","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101206","DOI":"10.1016\/j.molmet.2021.101206","article-title":"The melanocortin pathway and energy homeostasis: From discovery to obesity therapy","volume":"48","author":"Yeo","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lutz, T.A. (2020). An Overview of Rodent Models of Obesity and Type 2 Diabetes. Methods in Molecular Biology, Humana.","DOI":"10.1007\/978-1-0716-0385-7_2"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/S0092-8674(05)80067-4","article-title":"Molecular characterization of the mouse agouti locus","volume":"71","author":"Bultman","year":"1992","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2167","DOI":"10.1210\/endo.140.5.6748","article-title":"Agouti Antagonism of Melanocortin-4 Receptor: Greater Effect with Desacetyl-\u03b1-Melanocyte-Stimulating Hormone (MSH) than with \u03b1-MSH","volume":"140","author":"Mountjoy","year":"1999","journal-title":"Endocrinology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1152\/physiolgenomics.1999.1.3.151","article-title":"Physiological consequences of ectopic agouti gene expression: The yellow obese mouse syndrome","volume":"1","author":"Wolff","year":"1999","journal-title":"Physiol. Genom."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Derkach, K., Zakharova, I., Zorina, I., Bakhtyukov, A., Romanova, I., Bayunova, L., and Shpakov, A. (2019). The evidence of metabolic-improving effect of metformin in Ay\/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0213779"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"200","DOI":"10.18699\/VJ20.40-o","article-title":"Pharmacological effects of fibroblast growth factor 21 are sex-specific in mice with the lethal yellow (Ay) mutation","volume":"24","author":"Makarova","year":"2020","journal-title":"Vavilov J. Genet. Breed."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1038\/ijo.2017.50","article-title":"Hormone signaling and fatty liver in females: Analysis of estrogen receptor \u03b1 mutant mice","volume":"41","author":"Arao","year":"2017","journal-title":"Int. J. Obes."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.exger.2014.02.001","article-title":"Evidence for association of mitochondrial metabolism alteration with lipid accumulation in aging rats","volume":"56","author":"Zhao","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/0003-2697(74)90210-3","article-title":"Direct enzymatic procedure for the determination of liver glycogen","volume":"58","author":"Roehrig","year":"1974","journal-title":"Anal. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12339","DOI":"10.1073\/pnas.220409497","article-title":"A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors","volume":"97","author":"Marie","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1210\/en.2006-1389","article-title":"Role of the Central Melanocortin Circuitry in Adaptive Thermogenesis of Brown Adipose Tissue","volume":"148","author":"Murphy","year":"2007","journal-title":"Endocrinology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1210\/en.2003-0452","article-title":"Impaired Coordination of Nutrient Intake and Substrate Oxidation in Melanocortin-4 Receptor Knockout Mice","volume":"145","author":"Albarado","year":"2004","journal-title":"Endocrinology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1902S","DOI":"10.1093\/jn\/127.9.1902S","article-title":"The role of the agouti gene in the yellow obese syndrome","volume":"127","author":"Miltenberger","year":"1997","journal-title":"J. Nutr."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2274","DOI":"10.1007\/s00125-017-4389-x","article-title":"FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes","volume":"60","author":"Laeger","year":"2017","journal-title":"Diabetologia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.physbeh.2013.06.023","article-title":"Exaggerated anorexigenic response to restraint stress in Ay mice is associated with elevated CRFR2 mRNA expression in the hypothalamus","volume":"120","author":"Bazhan","year":"2013","journal-title":"Physiol. Behav."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.cmet.2014.07.012","article-title":"FGF21 Acts Centrally to Induce Sympathetic Nerve Activity, Energy Expenditure, and Weight Loss","volume":"20","author":"Owen","year":"2014","journal-title":"Cell Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"E822","DOI":"10.1152\/ajpendo.00270.2020","article-title":"Levels of \u03b2-klotho determine the thermogenic responsiveness of adipose tissues: Involvement of the autocrine action of FGF21","volume":"320","author":"Moure","year":"2021","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3424","DOI":"10.1016\/j.celrep.2020.02.055","article-title":"A Genetic Model to Study the Contribution of Brown and Brite Adipocytes to Metabolism","volume":"30","author":"Challa","year":"2020","journal-title":"Cell Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/nn.3737","article-title":"Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia","volume":"17","author":"Berglund","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.2337\/db17-1452","article-title":"Coordination among Lipid Droplets, Peroxisomes, and Mitochondria Regulates Energy Expenditure through the CIDE-ATGL-PPAR\u03b1 Pathway in Adipocytes","volume":"67","author":"Zhou","year":"2018","journal-title":"Diabetes"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.cmet.2017.03.005","article-title":"FGF21 Regulates Metabolism through Adipose-Dependent and -Independent Mechanisms","volume":"25","author":"BonDurant","year":"2017","journal-title":"Cell Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.molmet.2019.10.009","article-title":"Whole-body and adipose tissue-specific mechanisms underlying the metabolic effects of fibroblast growth factor 21 in the Siberian hamster","volume":"31","author":"Lewis","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1053\/j.gastro.2013.10.059","article-title":"Hepatic SIRT1 Attenuates Hepatic Steatosis and Controls Energy Balance in Mice by Inducing Fibroblast Growth Factor 21","volume":"146","author":"Li","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1210\/en.2013-1191","article-title":"Cellular Mechanisms by Which FGF21 Improves Insulin Sensitivity in Male Mice","volume":"154","author":"Camporez","year":"2013","journal-title":"Endocrinology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1152\/physiolgenomics.00125.2004","article-title":"Genetic influence on daily wheel running activity level","volume":"19","author":"Lightfoot","year":"2005","journal-title":"Physiol. Genom."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Goforth, P.B., and Myers, M.G. (2017). Roles for Orexin\/Hypocretin in the control of energy balance and metabolism. Current Topics in Behavioral Neurosciences, Springer.","DOI":"10.1007\/7854_2016_51"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.cld.2004.04.006","article-title":"Insulin resistance and the pathogenesis of nonalcoholic fatty liver disease","volume":"8","author":"Choudhury","year":"2004","journal-title":"Clin. Liver Dis."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Armandi, A., Rosso, C., Caviglia, G., and Bugianesi, E. (2021). Insulin Resistance across the Spectrum of Nonalcoholic Fatty Liver Disease. Metabolites, 11.","DOI":"10.3390\/metabo11030155"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e00772","DOI":"10.1016\/j.heliyon.2018.e00772","article-title":"Lack of 17\u03b2-estradiol reduces sensitivity to insulin in the liver and muscle of male mice","volume":"4","author":"Toda","year":"2018","journal-title":"Heliyon"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Khoramipour, K., Chamari, K., Hekmatikar, A.A., Ziyaiyan, A., Taherkhani, S., Elguindy, N.M., and Bragazzi, N.L. (2021). Adiponectin: Structure, physiological functions, role in diseases, and effects of nutrition. Nutrients, 13.","DOI":"10.3390\/nu13041180"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Garc\u00eda, I., Tena-Sempere, M., and L\u00f3pez, M. (2017). Estradiol regulation of brown adipose tissue thermogenesis. Advances in Experimental Medicine and Biology, Springer.","DOI":"10.1007\/978-3-319-70178-3_15"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4923","DOI":"10.1210\/en.2003-0537","article-title":"Direct Effects of Testosterone, 17\u03b2-Estradiol, and Progesterone on Adrenergic Regulation in Cultured Brown Adipocytes: Potential Mechanism for Gender-Dependent Thermogenesis","volume":"144","author":"Monjo","year":"2003","journal-title":"Endocrinology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"291","DOI":"10.2337\/db18-0638","article-title":"Estrogen Improves Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1","volume":"68","author":"Yan","year":"2019","journal-title":"Diabetes"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.pharmthera.2017.03.014","article-title":"Estradiol effects on hypothalamic AMPK and BAT thermogenesis: A gateway for obesity treatment?","volume":"178","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"113039","DOI":"10.1016\/j.physbeh.2020.113039","article-title":"Effects of metabolic state on the regulation of melanocortin circuits","volume":"224","author":"Lieu","year":"2020","journal-title":"Physiol. Behav."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.2337\/diabetes.52.9.2266","article-title":"Peripheral, but Not Central, Administration of Adiponectin Reduces Visceral Adiposity and Upregulates the Expression of Uncoupling Protein in Agouti Yellow (Ay\/a) Obese Mice","volume":"52","author":"Masaki","year":"2003","journal-title":"Diabetes"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"S157","DOI":"10.2337\/dc09-S302","article-title":"Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes","volume":"32","author":"DeFronzo","year":"2009","journal-title":"Diabetes Care"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1210\/en.2012-1989","article-title":"Cellular Mechanism by Which Estradiol Protects Female Ovariectomized Mice From High-Fat Diet-Induced Hepatic and Muscle Insulin Resistance","volume":"154","author":"Camporez","year":"2013","journal-title":"Endocrinology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.molmet.2017.04.011","article-title":"The glucoregulatory actions of leptin","volume":"6","author":"Neumann","year":"2017","journal-title":"Mol. Metab."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1126\/science.278.5343.1641","article-title":"Independent and Additive Effects of Central POMC and Leptin Pathways on Murine Obesity","volume":"278","author":"Boston","year":"1997","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s11892-013-0372-1","article-title":"Nuclear Factor (Erythroid-Derived 2)-Like-2 Factor (Nrf2), a Key Regulator of the Antioxidant Response to Protect Against Atherosclerosis and Nonalcoholic Steatohepatitis","volume":"13","author":"Gupte","year":"2013","journal-title":"Curr. Diabetes Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.3748\/wjg.v24.i25.2661","article-title":"Apoptosis and non-alcoholic fatty liver diseases","volume":"24","author":"Kanda","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1111\/febs.13665","article-title":"TGF-\u03b2 signalling and liver disease","volume":"283","author":"Fabregat","year":"2016","journal-title":"FEBS J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/s41598-017-00671-1","article-title":"TIMP-1 is upregulated, but not essential in hepatic fibrogenesis and carcinogenesis in mice","volume":"7","author":"Thiele","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"360","DOI":"10.3389\/fphys.2018.00360","article-title":"LiverSex Computational Model: Sexual Aspects in Hepatic Metabolism and Abnormalities","volume":"9","author":"Urlep","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1002\/hep.30626","article-title":"Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps","volume":"70","author":"Lonardo","year":"2019","journal-title":"Hepatology"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3440\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:42:21Z","timestamp":1760168541000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3440"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,7]]},"references-count":80,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cells10123440"],"URL":"https:\/\/doi.org\/10.3390\/cells10123440","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,7]]}}}