{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:55:30Z","timestamp":1790510130487,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,11,27]],"date-time":"2019-11-27T00:00:00Z","timestamp":1574812800000},"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>Fasting is often used for obesity correction but the \u201crefeeding syndrome\u201d limits its efficiency, and molecular mechanisms underlying metabolic response to different food availability are under investigation. Sex was shown to affect hormonal and metabolic reactions to fasting\/refeeding. The aim of this study was to evaluate hormonal and transcriptional responses to fasting and refeeding in male and female C57Bl\/6J mice. Sex asymmetry was observed both at the hormonal and transcriptional levels. Fasting (24 h) induced increase in hepatic Fgf21 gene expression, which was associated with elevation of plasma FGF21 and adiponectin levels, and the upregulation of expression of hepatic (Ppar\u03b1, Cpt1\u03b1) and muscle (Cpt1\u03b2, Ucp3) genes involved in fatty acid oxidation. These changes were more pronounced in females. Refeeding (6 h) evoked hyperinsulinemia and increased hepatic expression of gene related to lipogenesis (Fasn) only in males and hyperleptinemia and increase in Fgf21 gene expression in muscles and adipose tissues only in females. The results suggest that in mice, one of the molecular mechanisms underlying sex asymmetry in hepatic Ppar\u03b1, Cpt1\u03b1, muscle Cpt1\u03b2, and Ucp3 expression during fasting is hepatic Fgf21 expression, and the reason for sex asymmetry in hepatic Fasn expression during refeeding is male-specific hyperinsulinemia.<\/jats:p>","DOI":"10.3390\/cells8121529","type":"journal-article","created":{"date-parts":[[2019,11,27]],"date-time":"2019-11-27T11:07:00Z","timestamp":1574852820000},"page":"1529","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Sex Differences in Liver, Adipose Tissue, and Muscle Transcriptional Response to Fasting and Refeeding in Mice"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7246-4758","authenticated-orcid":false,"given":"Nadezhda","family":"Bazhan","sequence":"first","affiliation":[{"name":"The Laboratory of Physiological Genetics, The Institute of Cytology and Genetics, 630090 Novosibirsk, Russia"},{"name":"Department of Physiology, Novosibirsk State University, 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":"Feofanova","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"}]},{"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":"Natalia","family":"Sitnikova","sequence":"additional","affiliation":[{"name":"Department of Physiology, Novosibirsk State University, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6417-9893","authenticated-orcid":false,"given":"Elena","family":"Makarova","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":[[2019,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3389\/fendo.2014.00195","article-title":"Gender differences in skeletal muscle substrate metabolism\u2014Molecular mechanisms and insulin sensitivity","volume":"5","author":"Lundsgaard","year":"2014","journal-title":"Front. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13293-015-0033-y","article-title":"Sex differences in metabolic homeostasis, diabetes, and obesity","volume":"6","year":"2015","journal-title":"Biol. Sex Differ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-physiol-021115-105339","article-title":"Understanding the Physiology of FGF21","volume":"78","author":"Fisher","year":"2016","journal-title":"Annu. Rev. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1016\/j.bbadis.2018.04.004","article-title":"Sex differences in the development of hepatic steatosis in cafeteria diet-induced obesity in young mice","volume":"1864","author":"Gasparin","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1101\/gr.5217506","article-title":"Tissue-specific expression and regulation of sexually dimorphic genes in mice","volume":"16","author":"Yang","year":"2006","journal-title":"Genome Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gustavsson, C., Yassin, K., Wahlstr\u00f6m, E., Cheung, L., Lindberg, J., Brismar, K., Ostenson, C.-G., Norstedt, G., and Tollet-Egnell, P. (2010). Sex-different hepatic glycogen content and glucose output in rats. BMC Biochem., 11.","DOI":"10.1186\/1471-2091-11-38"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Benz, V., Bloch, M., Wardat, S., B\u00f6hm, C., Maurer, L., Mahmoodzadeh, S., Wiedmer, P., Spranger, J., Foryst-Ludwig, A., and Kintscher, U. (2012). Sexual dimorphic regulation of body weight dynamics and adipose tissue lipolysis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037794"},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.cmet.2007.05.002","article-title":"Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states","volume":"5","author":"Badman","year":"2007","journal-title":"Cell Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.cmet.2007.05.003","article-title":"Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21","volume":"5","author":"Inagaki","year":"2007","journal-title":"Cell Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10853","DOI":"10.1073\/pnas.0904187106","article-title":"FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response","volume":"106","author":"Potthoff","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","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_13","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_14","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_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1093\/cvr\/cvu263","article-title":"Fibroblast growth factor 21 protects the heart from oxidative stress","volume":"106","author":"Planavila","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.3844\/ojbsci.2019.28.36","article-title":"Sex dimorphism in the Fgf21 gene expression in liver and adipose tissues is dependent on the metabolic condition","volume":"19","author":"Bazhan","year":"2019","journal-title":"Online J. Biol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.molmet.2019.02.002","article-title":"Activation of hepatic estrogen receptor-\u03b1 increases energy expenditure by stimulating the production of fibroblast growth factor 21 in female mice","volume":"22","author":"Allard","year":"2019","journal-title":"Mol. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1038\/sj.ijo.0802135","article-title":"Gender difference in the leptin response to feeding in peroxisome-proliferator-activated receptor-alpha knockout mice","volume":"26","author":"Lewitt","year":"2002","journal-title":"Int. J. Obes. Relat. Metab. Disord."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.1161\/01.ATV.19.10.2448","article-title":"Gender difference in postprandial lipemia: Importance of visceral adipose tissue accumulation","volume":"19","author":"Couillard","year":"1999","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12983","DOI":"10.1074\/jbc.M110.215889","article-title":"Thermogenic activation induces FGF21 expression and release in brown adipose tissue","volume":"286","author":"Hondares","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1152\/ajpendo.90920.2008","article-title":"Lipoprotein lipase: From gene to obesity","volume":"297","author":"Wang","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1172\/JCI1244","article-title":"PPARgamma induces the insulin-dependent glucose transporter GLUT4 in the absence of C\/EBPalpha during the conversion of 3T3 fibroblasts into adipocytes","volume":"101","author":"Wu","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3175313","DOI":"10.1155\/2018\/3175313","article-title":"Increased mitochondrial protein levels and bioenergetics in the Musculus rectus femoris of Wfs1-deficient mice","volume":"2018","author":"Eimre","year":"2018","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1172\/JCI88893","article-title":"Nutrient-sensing nuclear receptors PPAR\u03b1 and FXR control liver energy balance","volume":"127","author":"Preidis","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.cmet.2016.04.011","article-title":"Adiponectin, leptin, and fatty acids in the maintenance of metabolic homeostasis through adipose tissue crosstalk","volume":"23","author":"Stern","year":"2016","journal-title":"Cell Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.bbrc.2007.06.068","article-title":"PPARalpha is a key regulator of hepatic FGF21","volume":"360","author":"Hunt","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1097\/gme.0b013e31817b8159","article-title":"Effects of ovariectomy on PPAR\u03b1, SREBP-1c, and SCD-1 gene expression in the rat liver","volume":"15","author":"Paquette","year":"2008","journal-title":"Menopause"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.molmet.2013.12.009","article-title":"Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice","volume":"3","author":"Kim","year":"2014","journal-title":"Mol. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11533","DOI":"10.1038\/ncomms11533","article-title":"Fasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p and suppression of PRDM16","volume":"7","author":"Ding","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12986-016-0159-x","article-title":"Plasticity of adipose tissue in response to fasting and refeeding in male mice","volume":"14","author":"Tang","year":"2017","journal-title":"Nutr. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.1210\/jc.2003-031327","article-title":"Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution","volume":"89","author":"Pedersen","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.diabres.2008.05.003","article-title":"Effect of fasting on PPARgamma and AMPK activity in adipocytes","volume":"81","author":"Kajita","year":"2008","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/aps.2010.198","article-title":"17\u03b2-Estradiol inhibition of PPAR\u03b3-induced adipogenesis and adipocyte-specific gene expression","volume":"32","author":"Jeong","year":"2011","journal-title":"Acta Pharm. Sin."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1054\/ghir.2001.0247","article-title":"Responses of insulin-like growth factor (IGF)-I and IGF-binding proteins to nutritional status in peroxisome proliferator-activated receptor-alpha knockout mice","volume":"11","author":"Lewitt","year":"2001","journal-title":"Growth Horm. IGF Res."},{"key":"ref_35","first-page":"1807","article-title":"Leptin concentrations, sex hormones, and cortisol in nondiabetic men","volume":"82","author":"Haffner","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_36","first-page":"3267","article-title":"Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals","volume":"82","author":"Elbers","year":"1997","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8232","DOI":"10.1038\/s41598-017-07473-5","article-title":"Sex steroid hormones regulate leptin transcript accumulation and protein secretion in 3T3-L1 cells","volume":"7","author":"Jenks","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1046\/j.1432-1327.1999.00183.x","article-title":"Transcriptional regulation of fatty acid synthase gene by insulin\/glucose, polyunsaturated fatty acid and leptin in hepatocytes and adipocytes in normal and genetically obese rats","volume":"260","author":"Fukuda","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1042\/bst0290552","article-title":"Insulin-regulated gene expression","volume":"29","author":"Streeper","year":"2001","journal-title":"Biochem. Soc. Trans."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.cell.2011.11.062","article-title":"Fibroblast growth factor-21 regulates PPAR\u03b3 activity and the antidiabetic actions of thiazolidinediones","volume":"148","author":"Dutchak","year":"2012","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1124\/mol.108.044826","article-title":"Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic states","volume":"74","author":"Muise","year":"2008","journal-title":"Mol. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.2337\/db09-0713","article-title":"Fibroblast growth factor-21 is induced in human skeletal muscles by hyperinsulinemia","volume":"58","author":"Hojman","year":"2009","journal-title":"Diabetes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S1550-8579(07)80049-0","article-title":"Sexually dimorphic gene expression in mammalian somatic tissue","volume":"4","author":"Isensee","year":"2007","journal-title":"Gend. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1529\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:38:04Z","timestamp":1760189884000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/12\/1529"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,27]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["cells8121529"],"URL":"https:\/\/doi.org\/10.3390\/cells8121529","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,27]]}}}