{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:20:25Z","timestamp":1790659225274,"version":"4.1.0"},"reference-count":85,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T00:00:00Z","timestamp":1766534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibroblast growth factor 21 (FGF21) is a key hormone for metabolic homeostasis under conditions such as obesity, aging and diabetes. While extensively studied in males, its role in female physiology remains poorly defined. This study evaluated the effects of hepatic FGF21 deletion in 12-month-old female mice using a liver-specific FGF21 knockout (FKO) model. FKO females exhibited reduced body weight and improved glucose tolerance, with no changes in circulating FGF21 levels. In the liver, RT-qPCR analysis showed that the expression of genes involved in de novo lipogenesis, including Srebp1c, Fasn, and Scd1, was downregulated, whereas markers of fatty acid uptake (Cd36) and \u03b2-oxidation (Cpt1a) were upregulated without alterations in hepatic triglyceride content and lower levels of serum adiponectin. Remarkably, telomere length in both liver and adipose tissue was preserved, indicating improved cellular aging. Hepatic transcriptomic analysis revealed a global downregulation of genes linked to cytoskeletal organization, immune processes and fibrosis. Among these, Chrna4, a hepatocyte-specific nicotinic acetylcholine receptor subunit implicated in protection against metabolic-associated steatohepatitis (MASH), was significantly reduced. These findings suggest that hepatic FGF21 deficiency in aged female mice promotes metabolic health by limiting pro-inflammatory and fibrotic pathways and preserving telomere integrity, with Chrna4 emerging as a potential mediator.<\/jats:p>","DOI":"10.3390\/ijms27010194","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T09:58:34Z","timestamp":1766570314000},"page":"194","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hepatic FGF21 Deletion Improves Glucose Metabolism, Alters Lipogenic and Chrna4 Gene Expression, and Enhances Telomere Maintenance in Aged Female Mice"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0445-028X","authenticated-orcid":false,"given":"Daniel","family":"Torres-Oteros","sequence":"first","affiliation":[{"name":"Department of Nutrition, Food Sciences and Gastronomy, School of Pharmacy and Food Sciences, Food 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Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s13105-019-00675-7","article-title":"FGF19 Subfamily Members: FGF19 and FGF21","volume":"75","author":"Dolegowska","year":"2019","journal-title":"J. Physiol. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/j.cmet.2012.08.002","article-title":"\u0392Kslotho Is Required for Fibroblast Growth Factor 21 Effects on Growth and Metabolism","volume":"16","author":"Ding","year":"2012","journal-title":"Cell Metab."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"20160034","DOI":"10.1515\/hmbci-2016-0034","article-title":"Nutritional Regulation of Fibroblast Growth Factor 21: From Macronutrients to Bioactive Dietary Compounds","volume":"30","author":"Sandoval","year":"2017","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.2337\/db10-0193","article-title":"Obesity Is a Fibroblast Growth Factor 21 (FGF21)-Resistant State","volume":"59","author":"Fisher","year":"2010","journal-title":"Diabetes"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"289","DOI":"10.12688\/f1000research.14117.1","article-title":"Defining \u201cFGF21 Resistance\u201d during Obesity: Controversy, Criteria and Unresolved Questions","volume":"7","author":"Markan","year":"2018","journal-title":"F1000Res"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1210\/en.2017-00056","article-title":"Letter to the Editor: Parameters, Characteristics, and Criteria for Defining the Term \u201cFGF21 Resistance\u201d","volume":"158","author":"Tanajak","year":"2017","journal-title":"Endocrinology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.arr.2017.05.004","article-title":"Regulation of Longevity by FGF21: Interaction between Energy Metabolism and Stress Responses","volume":"37","author":"Salminen","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1159\/000454924","article-title":"Energy Metabolism and Ageing in the Mouse: A Mini-Review","volume":"63","author":"Azzu","year":"2017","journal-title":"Gerontology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/350569a0","article-title":"Structure and Function of Telomeres","volume":"350","author":"Blackburn","year":"1991","journal-title":"Nature"},{"key":"ref_13","first-page":"28","article-title":"Telomeres, Lifestyle, Cancer, and Aging","volume":"14","author":"Shammas","year":"2011","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cell.2020.12.028","article-title":"Telomeres: History, Health, and Hallmarks of Aging","volume":"184","author":"Chakravarti","year":"2021","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gavia-Garc\u00eda, G., Rosado-P\u00e9rez, J., Arista-Ugalde, T.L., Agui\u00f1iga-S\u00e1nchez, I., Santiago-Osorio, E., and Mendoza-N\u00fa\u00f1ez, V.M. (2021). Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging. Biology, 10.","DOI":"10.3390\/biology10040253"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e12991","DOI":"10.1111\/obr.12991","article-title":"Obesity and Ageing: Two Sides of the Same Coin","volume":"21","author":"Tam","year":"2020","journal-title":"Obes. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1001\/jama.289.2.187","article-title":"Years of Life Lost Due to Obesity","volume":"289","author":"Fontaine","year":"2003","journal-title":"JAMA"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yan, J., Nie, Y., Cao, J., Luo, M., Yan, M., Chen, Z., and He, B. (2021). The Roles and Pharmacological Effects of FGF21 in Preventing Aging-Associated Metabolic Diseases. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.655575"},{"key":"ref_19","first-page":"72","article-title":"Circulating Levels of Fibroblast Growth Factor-21 Increase with Age Independently of Body Composition Indices among Healthy Individuals","volume":"2","author":"Hanks","year":"2015","journal-title":"J. Clin. Transl. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e12822","DOI":"10.1111\/acel.12822","article-title":"Aging Is Associated with Increased FGF21 Levels but Unaltered FGF21 Responsiveness in Adipose Tissue","volume":"17","author":"Villarroya","year":"2018","journal-title":"Aging Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.exger.2019.01.001","article-title":"Impact of Aging and Caloric Restriction on Fibroblast Growth Factor 21 Signaling in Rat White Adipose Tissue","volume":"118","author":"Fujii","year":"2019","journal-title":"Exp. Gerontol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/s41434-023-00422-0","article-title":"Long-Term Effects of a Fat-Directed FGF21 Gene Therapy in Aged Female Mice","volume":"31","author":"Anderson","year":"2024","journal-title":"Gene Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cmet.2008.05.006","article-title":"Inhibition of Growth Hormone Signaling by the Fasting-Induced Hormone FGF21","volume":"8","author":"Inagaki","year":"2008","journal-title":"Cell Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00065","DOI":"10.7554\/eLife.00065","article-title":"The Starvation Hormone, Fibroblast Growth Factor-21, Extends Lifespan in Mice","volume":"1","author":"Zhang","year":"2012","journal-title":"eLife"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of Aging: An Expanding Universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/j.cmet.2016.05.027","article-title":"Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice","volume":"23","author":"Mitchell","year":"2016","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3477","DOI":"10.1210\/en.2017-00331","article-title":"Sex Differences in the Hormonal and Metabolic Response to Dietary Protein Dilution","volume":"158","author":"Larson","year":"2017","journal-title":"Endocrinology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.cmet.2021.12.018","article-title":"Sex and Genetic Background Define the Metabolic, Physiologic, and Molecular Response to Protein Restriction","volume":"34","author":"Green","year":"2022","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bazhan, N., Jakovleva, T., Feofanova, N., Denisova, E., Dubinina, A., Sitnikova, N., and Makarova, E. (2019). Sex Differences in Liver, Adipose Tissue, and Muscle Transcriptional Response to Fasting and Refeeding in Mice. Cells, 8.","DOI":"10.3390\/cells8121529"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Makarova, E., Kazantseva, A., Dubinina, A., Denisova, E., Jakovleva, T., Balybina, N., Bgatova, N., Baranov, K., and Bazhan, N. (2021). Fibroblast Growth Factor 21 (Fgf21) Administration Sex-Specifically Affects Blood Insulin Levels and Liver Steatosis in Obese Ay Mice. Cells, 10.","DOI":"10.3390\/cells10123440"},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"R290","DOI":"10.1152\/ajpregu.00554.2013","article-title":"Hepatic FGF21 Production Is Increased in Late Pregnancy in the Mouse","volume":"307","author":"Cui","year":"2014","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Buell-Acosta, J.D., Garces, M.F., Parada-Ba\u00f1os, A.J., Angel-Muller, E., Paez, M.C., Eslava-Schmalbach, J., Escobar-Cordoba, F., Caminos-Cepeda, S.A., Lacunza, E., and Casta\u00f1o, J.P. (2022). Maternal Fibroblast Growth Factor 21 Levels Decrease during Early Pregnancy in Normotensive Pregnant Women but Are Higher in Preeclamptic Women\u2014A Longitudinal Study. Cells, 11.","DOI":"10.3390\/cells11142251"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12986-021-00570-3","article-title":"Changes in Hepatic Triglyceride Content with the Activation of ER Stress and Increased FGF21 Secretion during Pregnancy","volume":"18","author":"Lu","year":"2021","journal-title":"Nutr. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1055\/a-1778-4159","article-title":"FGF21: A Novel Regulator of Glucose and Lipid Metabolism and Whole-Body Energy Balance","volume":"54","year":"2022","journal-title":"Horm. Metab. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gamberi, T., Magherini, F., Modesti, A., and Fiaschi, T. (2018). Adiponectin Signaling Pathways in Liver Diseases. Biomedicines, 6.","DOI":"10.3390\/biomedicines6020052"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"12553","DOI":"10.1073\/pnas.1006962107","article-title":"Fibroblast Growth Factor 21 Regulates Energy Metabolism by Activating the AMPK-SIRT1-PGC-1\u03b1 Pathway","volume":"107","author":"Chau","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Akk\u0131z, H., Gieseler, R.K., and Canbay, A. (2024). Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202405.1666.v1"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Xu, J., Liu, X., Koyama, Y., Wang, P., Lan, T., Kim, I.-G., Kim, I.H., Ma, H.-Y., and Kisseleva, T. (2014). The Types of Hepatic Myofibroblasts Contributing to Liver Fibrosis of Different Etiologies. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00167"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.cytogfr.2013.08.002","article-title":"ALK1-Smad1\/5 Signaling Pathway in Fibrosis Development: Friend or Foe?","volume":"24","year":"2013","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1053\/j.gastro.2004.07.007","article-title":"Regulation of Hepatic Stellate Cell Activation and Growth by Transcription Factor Myocyte Enhancer Factor 2","volume":"127","author":"Wang","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4748","DOI":"10.1038\/s41598-017-05044-2","article-title":"Characterization of Transcriptional Modules Related to Fibrosing-NAFLD Progression","volume":"7","author":"Lou","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41419-022-04802-z","article-title":"MyD88 in Hepatic Stellate Cells Enhances Liver Fibrosis via Promoting Macrophage M1 Polarization","volume":"13","author":"Zhang","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1016\/j.cmet.2023.10.018","article-title":"Hepatocyte CHRNA4 Mediates the MASH-Promotive Effects of Immune Cell-Produced Acetylcholine and Smoking Exposure in Mice and Humans","volume":"35","author":"Pan","year":"2023","journal-title":"Cell Metab."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cellsig.2017.08.009","article-title":"Integrated Stress Response Stimulates FGF21 Expression: Systemic Enhancer of Longevity","volume":"40","author":"Salminen","year":"2017","journal-title":"Cell Signal"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.1172\/JCI74915","article-title":"FGF21 Is an Endocrine Signal of Protein Restriction","volume":"124","author":"Laeger","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1194\/jlr.M033415","article-title":"FGF21 Mediates the Lipid Metabolism Response to Amino Acid Starvation","volume":"54","author":"Relat","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1600725","DOI":"10.1002\/mnfr.201600725","article-title":"A Low-Protein Diet Induces Body Weight Loss and Browning of Subcutaneous White Adipose Tissue through Enhanced Expression of Hepatic Fibroblast Growth Factor 21 (FGF21)","volume":"61","author":"Estruch","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e11490","DOI":"10.1016\/j.heliyon.2022.e11490","article-title":"FGF21 Negatively Affects Long-Term Female Fertility in Mice","volume":"8","author":"Moeckli","year":"2022","journal-title":"Heliyon"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1038\/nm.3250","article-title":"FGF21 Contributes to Neuroendocrine Control of Female Reproduction","volume":"19","author":"Owen","year":"2013","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"E292","DOI":"10.1152\/ajpendo.00638.2020","article-title":"Estrogen-Wnt Signaling Cascade Regulates Expression of Hepatic Fibroblast Growth Factor 21","volume":"321","author":"Badakhshi","year":"2021","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Cao, Y., Yang, M., Song, J., Jiang, X., Xu, S., Che, L., Fang, Z., Lin, Y., Jin, C., and Feng, B. (2023). Dietary Protein Regulates Female Estrous Cyclicity Partially via Fibroblast Growth Factor 21. Nutrients, 15.","DOI":"10.3390\/nu15133049"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.bbrc.2015.12.045","article-title":"Differentiated Embryo Chondrocyte 1 (DEC1) Is a Novel Negative Regulator of Hepatic Fibroblast Growth Factor 21 (FGF21) in Aging Mice","volume":"469","author":"Fujita","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1093\/gerona\/gly153","article-title":"Human Aging and Longevity Are Characterized by High Levels of Mitokines","volume":"74","author":"Conte","year":"2019","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"101507","DOI":"10.1016\/j.arr.2021.101507","article-title":"Stress and Telomere Shortening: Insights from Cellular Mechanisms","volume":"73","author":"Lin","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1053\/j.seminhematol.2013.03.030","article-title":"Telomere Dynamics in Mice and Humans","volume":"50","author":"Calado","year":"2013","journal-title":"Semin. Hematol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mad.2018.03.013","article-title":"The Impact of Oxidative DNA Damage and Stress on Telomere Homeostasis","volume":"177","author":"Barnes","year":"2019","journal-title":"Mech. Ageing Dev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1093\/ije\/dyv165","article-title":"Leukocyte Telomere Length Dynamics in Women and Men: Menopause vs Age Effects","volume":"44","author":"Benetos","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.exger.2013.12.004","article-title":"Gender and Telomere Length: Systematic Review and Meta-Analysis","volume":"51","author":"Gardner","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"hoae062","DOI":"10.1093\/hropen\/hoae062","article-title":"Sperm and Leukocyte Telomere Length Are Related to Sperm Quality Parameters in Healthy Men from the Led-Fertyl Study","volume":"2024","author":"Canudas","year":"2024","journal-title":"Hum. Reprod. Open"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Choe, S.S., Huh, J.Y., Hwang, I.J., Kim, J.I., and Kim, J.B. (2016). Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders. Front. Endocrinol., 7.","DOI":"10.3389\/fendo.2016.00030"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1002\/j.2040-4603.2018.tb00036.x","article-title":"Adiponectin Regulation and Function","volume":"8","author":"Fang","year":"2018","journal-title":"Compr. Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1096\/fj.11-194019","article-title":"Sustained Activation of PPAR\u03b1 by Endogenous Ligands Increases Hepatic Fatty Acid Oxidation and Prevents Obesity in Ob\/Ob. Mice","volume":"26","author":"Huang","year":"2012","journal-title":"FASEB J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"110910","DOI":"10.1016\/j.celrep.2022.110910","article-title":"ATGL-Dependent White Adipose Tissue Lipolysis Controls Hepatocyte PPAR\u03b1 Activity","volume":"39","author":"Fougerat","year":"2022","journal-title":"Cell Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.bbrc.2007.06.068","article-title":"PPAR\u03b1 Is a Key Regulator of Hepatic FGF21","volume":"360","author":"Hunt","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1210\/en.2003-1068","article-title":"A Transgenic Mouse with a Deletion in the Collagenous Domain of Adiponectin Displays Elevated Circulating Adiponectin and Improved Insulin Sensitivity","volume":"145","author":"Combs","year":"2004","journal-title":"Endocrinology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3892\/br.2013.206","article-title":"Effects of Aging on the Plasma Levels of Nesfatin-1 and Adiponectin","volume":"2","author":"Li","year":"2014","journal-title":"Biomed. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"11473","DOI":"10.3390\/ijms150711473","article-title":"Biochemical Alterations during the Obese-Aging Process in Female and Male Monosodium Glutamate (MSG)-Treated Mice","volume":"15","author":"Fainstein","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Tillman, E.J., and Rolph, T. (2020). FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.601290"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e83075","DOI":"10.7554\/eLife.83075","article-title":"FGF21 Protects against Hepatic Lipotoxicity and Macrophage Activation to Attenuate Fibrogenesis in Nonalcoholic Steatohepatitis","volume":"12","author":"Liu","year":"2023","journal-title":"eLife"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"107634","DOI":"10.1016\/j.intimp.2021.107634","article-title":"FGF21 Alleviates Chronic Inflammatory Injury in the Aging Process through Modulating Polarization of Macrophages","volume":"96","author":"Kang","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.taap.2015.11.012","article-title":"Fibroblast Growth Factor 21 Attenuates Hepatic Fibrogenesis through TGF-\u03b2\/Smad2\/3 and NF-\u039aB Signaling Pathways","volume":"290","author":"Xu","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.2337\/db20-0209","article-title":"The Effects of B1344, a Novel Fibroblast Growth Factor 21 Analog, on Nonalcoholic Steatohepatitis in Nonhuman Primates","volume":"69","author":"Cui","year":"2020","journal-title":"Diabetes"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"EMMM201708791","DOI":"10.15252\/emmm.201708791","article-title":"FGF21 Gene Therapy as Treatment for Obesity and Insulin Resistance","volume":"10","author":"Jimenez","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.addr.2017.05.007","article-title":"Hepatic Stellate Cells as Key Target in Liver Fibrosis","volume":"121","author":"Higashi","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","article-title":"Mechanisms of Hepatic Stellate Cell Activation","volume":"14","author":"Tsuchida","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Zhang, B., Madden, P., Gu, J., Xing, X., Sankar, S., Flynn, J., Kroll, K., and Wang, T. (2017). Uncovering the Transcriptomic and Epigenomic Landscape of Nicotinic Receptor Genes in Non-Neuronal Tissues. BMC Genom., 18.","DOI":"10.1186\/s12864-017-3813-4"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.cmet.2016.01.006","article-title":"FGF21 Lowers Plasma Triglycerides by Accelerating Lipoprotein Catabolism in White and Brown Adipose Tissues","volume":"23","author":"Schlein","year":"2016","journal-title":"Cell Metab."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e155848","DOI":"10.1172\/jci.insight.155848","article-title":"FGF21 Controls Hepatic Lipid Metabolism via Sex-Dependent Interorgan Crosstalk","volume":"7","author":"Chaffin","year":"2022","journal-title":"JCI Insight"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Xu, J., Shao, X., Zeng, H., Wang, C., Li, J., Peng, X., Zhuo, Y., Hua, L., Meng, F., and Han, X. (2023). Hepatic-Specific FGF21 Knockout Abrogates Ovariectomy-Induced Obesity by Reversing Corticosterone Production. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241914922"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"46959","DOI":"10.18632\/oncotarget.10506","article-title":"Sex-Specific Metabolic Interactions between Liver and Adipose Tissue in MCD Diet-Induced Non-Alcoholic Fatty Liver Disease","volume":"7","author":"Lee","year":"2016","journal-title":"Oncotarget"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1038\/s41366-022-01174-4","article-title":"Sex-Specific Changes in Metabolism during the Transition from Chow to High-Fat Diet Feeding Are Abolished in Response to Dieting in C57BL\/6J Mice","volume":"46","author":"Oraha","year":"2022","journal-title":"Int. J. Obes."},{"key":"ref_83","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"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Kamiya, A., and Ida, K. (2022). Liver Injury and Cell Survival in Non-Alcoholic Steatohepatitis Regulated by Sex-Based Difference through B Cell Lymphoma 6. Cells, 11.","DOI":"10.3390\/cells11233751"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"807","DOI":"10.2144\/000112761","article-title":"A Quantitative Real-Time PCR Method for Absolute Telomere Length","volume":"44","author":"Dhillon","year":"2008","journal-title":"Biotechniques"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/194\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T05:17:04Z","timestamp":1766726224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/194"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,24]]},"references-count":85,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010194"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010194","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,24]]}}}