{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:04:55Z","timestamp":1786115095909,"version":"build-2736575974"},"reference-count":58,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"the Sugar Industry Association"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Obesity and alcoholism are major global health burdens driven in part by maladaptive ingestive behaviours. Accordingly, functional foods that curb overeating and excessive alcohol consumption may help prevent these disorders. Ingestion of simple sugars or alcohol increases plasma fibroblast growth factor 21 (FGF21), which activates oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVH) and suppresses the specific appetite for sugar and alcohol. d-Allulose and d-tagatose are generally recognized as safe rare sugars and serve as potent inducers of FGF21. Oral administration of these sugars elevates plasma FGF21 to levels sufficient to reduce preference for simple sugars and alcohol without altering palatability. In mice, they also prevent the development of diet-induced obesity and alcohol dependence. Mechanistically, these effects involve activating transcription factor 4-dependent induction of FGF21 and activation of the FGF21-PVHOXT negative feedback system. Thus, rare sugars such as d-allulose and d-tagatose may improve ingestive behaviours and help prevent obesity and alcoholism.<\/jats:p>","DOI":"10.1093\/jb\/mvag059","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T11:43:16Z","timestamp":1784893396000},"source":"Crossref","is-referenced-by-count":0,"title":["FGF21-inducing rare sugars for addressing obesity and alcoholism"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8041-1915","authenticated-orcid":false,"given":"Tsutomu","family":"Sasaki","sequence":"first","affiliation":[{"name":"Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"2026080520363606300_ref1","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/S0140-6736(20)30752-2","article-title":"Global burden of 87 risk factors in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019","volume":"396","author":"GBD Risk Factors Collaborators","year":"2020","journal-title":"Lancet."},{"key":"2026080520363606300_ref2","doi-asserted-by":"crossref","DOI":"10.1111\/adb.13206","article-title":"Compulsive-like eating of high-fat high-sugar food is associated with \u2018addiction-like\u2019 glutamatergic dysfunction in obesity prone rats","volume":"27","author":"Sketriene","year":"2022","journal-title":"Addict. Biol."},{"key":"2026080520363606300_ref3","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1056\/NEJMoa1614362","article-title":"Health effects of overweight and obesity in 195 countries over 25 years","volume":"377","author":"GBD 2015 Obesity Collaborators","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"2026080520363606300_ref4","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1002\/oby.23725","article-title":"Estimated minimum prices and lowest available national prices for antiobesity medications: improving affordability and access to treatment","volume":"31","author":"Levi","year":"2023","journal-title":"Obesity (Silver Spring)"},{"key":"2026080520363606300_ref5","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/S0140-6736(18)31310-2","article-title":"Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016","volume":"392","author":"GBD (2016) Alcohol Collaborators","year":"2018","journal-title":"Lancet."},{"key":"2026080520363606300_ref6","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s41572-022-00406-1","article-title":"Hazardous drinking and alcohol use disorders","volume":"8","author":"MacKillop","year":"2022","journal-title":"Nat. Rev. Dis. Primers"},{"key":"2026080520363606300_ref7","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0140-6736(22)00847-9","volume":"400","author":"GBD (2020) Alcohol collaborators","year":"2022","journal-title":"Lancet."},{"key":"2026080520363606300_ref8","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1146\/annurev-pharmtox-031323-115847","article-title":"Alcohol use disorder treatment: problems and solutions","volume":"64","author":"Koob","year":"2024","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"2026080520363606300_ref9","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1080\/14728214.2024.2342951","article-title":"Emerging drugs in phase II and III clinical development for the treatment of alcohol use disorder","volume":"29","author":"Kohne","year":"2024","journal-title":"Expert Opin. Emerg. Drugs."},{"key":"2026080520363606300_ref10","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.cmet.2019.01.004","article-title":"A dozen years of discovery: insights into the physiology and pharmacology of FGF21","volume":"29","author":"Kliewer","year":"2019","journal-title":"Cell Metab."},{"key":"2026080520363606300_ref11","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1093\/hmg\/ddt032","article-title":"Novel locus including FGF21 is associated with dietary macronutrient intake","volume":"22","author":"Chu","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"2026080520363606300_ref12","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.3945\/ajcn.112.052183","article-title":"Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake","volume":"97","author":"Tanaka","year":"2013","journal-title":"Am. J. Clin. Nutr."},{"key":"2026080520363606300_ref13","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1038\/s41380-018-0079-4","article-title":"Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium","volume":"24","author":"Merino","year":"2019","journal-title":"Mol. Psychiatry"},{"key":"2026080520363606300_ref14","doi-asserted-by":"crossref","first-page":"2056","DOI":"10.1038\/s41380-020-0697-5","article-title":"Genomic analysis of diet composition finds novel loci and associations with health and lifestyle","volume":"26","author":"Meddens","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"2026080520363606300_ref15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41562-021-01182-w","article-title":"Genetic analysis of dietary intake identifies new loci and functional links with metabolic traits","volume":"6","author":"Merino","year":"2022","journal-title":"Nat. Hum. Behav."},{"key":"2026080520363606300_ref16","doi-asserted-by":"crossref","first-page":"14372","DOI":"10.1073\/pnas.1611243113","article-title":"KLB is associated with alcohol drinking, and its gene product beta-Klotho is necessary for FGF21 regulation of alcohol preference","volume":"113","author":"Schumann","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026080520363606300_ref17","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.cmet.2017.04.009","article-title":"FGF21 is a sugar-induced hormone associated with sweet intake and preference in humans","volume":"25","author":"Soberg","year":"2017","journal-title":"Cell Metab."},{"key":"2026080520363606300_ref18","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1016\/j.molmet.2017.08.004","article-title":"Fibroblast growth factor 21 (FGF21) is robustly induced by ethanol and has a protective role in ethanol associated liver injury","volume":"6","author":"Desai","year":"2017","journal-title":"Mol. Metab."},{"key":"2026080520363606300_ref19","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.molmet.2018.03.010","article-title":"FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest","volume":"11","author":"Soberg","year":"2018","journal-title":"Mol. Metab."},{"key":"2026080520363606300_ref20","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1530\/EC-19-0317","article-title":"Gluco-metabolic effects of oral and intravenous alcohol administration in men","volume":"8","author":"Lanng","year":"2019","journal-title":"Endocr. Connect."},{"key":"2026080520363606300_ref21","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cmet.2015.12.008","article-title":"FGF21 regulates sweet and alcohol preference","volume":"23","author":"Talukdar","year":"2016","journal-title":"Cell Metab."},{"key":"2026080520363606300_ref22","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.cmet.2015.12.003","article-title":"FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver","volume":"23","author":"Holstein-Rathlou","year":"2016","journal-title":"Cell Metab."},{"key":"2026080520363606300_ref23","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1002\/cne.24668","article-title":"The central fibroblast growth factor receptor\/beta klotho system: comprehensive mapping in Mus musculus and comparisons to nonhuman primate and human samples using an automated in situ hybridization platform","volume":"527","author":"Hultman","year":"2019","journal-title":"J. Comp. Neurol."},{"key":"2026080520363606300_ref24","doi-asserted-by":"crossref","first-page":"4604","DOI":"10.1038\/s41467-018-07033-z","article-title":"Neuronal SIRT1 regulates macronutrient-based diet selection through FGF21 and oxytocin signalling in mice","volume":"9","author":"Matsui","year":"2018","journal-title":"Nat. Commun."},{"key":"2026080520363606300_ref25","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2525172122","article-title":"Negative feedback regulation of alcohol ingestion through the FGF21-PVH oxytocin-VTA dopamine system","volume":"123","author":"Matsui","year":"2026","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2026080520363606300_ref26","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cmet.2020.06.008","article-title":"FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake","volume":"32","author":"Jensen-Cody","year":"2020","journal-title":"Cell Metab."},{"key":"2026080520363606300_ref27","doi-asserted-by":"crossref","first-page":"E18","DOI":"10.1152\/ajpendo.00138.2025","article-title":"Promotion of obesity by fibroblast growth factor 21-oxytocin system dysfunction due to sugar-specific hyperphagia","volume":"329","author":"Mori","year":"2025","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2026080520363606300_ref28","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cmet.2021.12.024","article-title":"FGF21 suppresses alcohol consumption through an amygdalo-striatal circuit","volume":"34","author":"Flippo","year":"2022","journal-title":"Cell Metab."},{"key":"2026080520363606300_ref29","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S1389-1723(04)70173-5","article-title":"Izumoring: a novel and complete strategy for bioproduction of rare sugars","volume":"97","author":"Granstrom","year":"2004","journal-title":"J. Biosci. Bioeng."},{"key":"2026080520363606300_ref30","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/nutrit\/nuab012","article-title":"Rare sugars and their health effects in humans: a systematic review and narrative synthesis of the evidence from human trials","volume":"80","author":"Ahmed","year":"2022","journal-title":"Nutr. Rev."},{"key":"2026080520363606300_ref31","doi-asserted-by":"crossref","first-page":"E578","DOI":"10.1152\/ajpendo.00365.2018","article-title":"Lipid and glucose metabolism in hepatocyte cell lines and primary mouse hepatocytes: a comprehensive resource for in vitro studies of hepatic metabolism","volume":"316","author":"Nagarajan","year":"2019","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2026080520363606300_ref32","doi-asserted-by":"crossref","DOI":"10.14814\/phy2.70618","article-title":"Identification of FGF21-inducing rare sugars that reduces sugar appetite in male BL\/6 mice","volume":"13","author":"Efendi","year":"2025","journal-title":"Physiol. Rep."},{"key":"2026080520363606300_ref33","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0022976","article-title":"Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor?","volume":"6","author":"Uebanso","year":"2011","journal-title":"PLoS One"},{"key":"2026080520363606300_ref34","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1507\/endocrj.EJ25-0549","article-title":"Fibroblast growth factor 21-inducing rare sugars prevent diet-induced obesity in male BL\/6 mice","volume":"73","author":"Efendi","year":"2026","journal-title":"Endocr. J."},{"key":"2026080520363606300_ref35","first-page":"1955","article-title":"Intestinal absorption, organ distribution, and urinary excretion of the rare sugar D-psicose","volume":"8","author":"Tsukamoto","year":"2014","journal-title":"Drug Des. Devel. Ther."},{"key":"2026080520363606300_ref36","doi-asserted-by":"crossref","first-page":"448","DOI":"10.3390\/foods8100448","article-title":"Metabolic stability of D-allulose in biorelevant media and hepatocytes: comparison with fructose and erythritol","volume":"8","author":"Maeng","year":"2019","journal-title":"Foods."},{"key":"2026080520363606300_ref37","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1006\/rtph.1998.1251","article-title":"Disposition of D-[U-14C]tagatose in the rat","volume":"29","author":"Saunders","year":"1999","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"2026080520363606300_ref38","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1053\/meta.2000.9532","article-title":"Effects of oral D-tagatose, a stereoisomer of D-fructose, on liver metabolism in man as examined by 31P-magnetic resonance spectroscopy","volume":"49","author":"Buemann","year":"2000","journal-title":"Metabolism."},{"key":"2026080520363606300_ref39","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"2026080520363606300_ref40","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.3390\/nu10122010","article-title":"Gastrointestinal tolerance of D-allulose in healthy and young adults. A non-randomized controlled trial","volume":"10","author":"Han","year":"2018","journal-title":"Nutrients."},{"key":"2026080520363606300_ref41","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.toxrep.2022.03.028","article-title":"Teratogenicity of D-allulose","volume":"9","author":"Sa","year":"2022","journal-title":"Toxicol. Rep."},{"key":"2026080520363606300_ref42","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/j.1460-2075.1984.tb01775.x","article-title":"Four secretory proteins synthesized by hepatocytes are transported from endoplasmic reticulum to Golgi complex at different rates","volume":"3","author":"Fries","year":"1984","journal-title":"EMBO J."},{"key":"2026080520363606300_ref43","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":"2026080520363606300_ref44","doi-asserted-by":"crossref","first-page":"3730","DOI":"10.1038\/s41598-019-40359-2","article-title":"B-cell translocation gene 2 enhances fibroblast growth factor 21 production by inducing Kruppel-like factor 15","volume":"9","author":"Kim","year":"2019","journal-title":"Sci. Rep."},{"key":"2026080520363606300_ref45","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1210\/en.2013-1490","article-title":"Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor alpha to regulate metabolic hormone FGF21","volume":"155","author":"Kim","year":"2014","journal-title":"Endocrinology."},{"key":"2026080520363606300_ref46","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1016\/j.febslet.2009.07.053","article-title":"Glucose induces FGF21 mRNA expression through ChREBP activation in rat hepatocytes","volume":"583","author":"Iizuka","year":"2009","journal-title":"FEBS Lett."},{"key":"2026080520363606300_ref47","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.biochi.2012.10.019","article-title":"Fibroblast growth factor 21 is induced by endoplasmic reticulum stress","volume":"95","author":"Schaap","year":"2013","journal-title":"Biochimie."},{"key":"2026080520363606300_ref48","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1080\/09168451.2015.1135045","article-title":"Fibroblast growth factor 21 induction by activating transcription factor 4 is regulated through three amino acid response elements in its promoter region","volume":"80","author":"Maruyama","year":"2016","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"2026080520363606300_ref49","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/bbb\/zbaf147","article-title":"Activating transcription factor 4 mediates rare sugar-induced transactivation of the fibroblast growth factor 21 promoter","volume":"90","author":"Efendi","year":"2025","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"2026080520363606300_ref50","doi-asserted-by":"crossref","first-page":"15378","DOI":"10.1074\/jbc.M116.715151","article-title":"Hepatic aryl hydrocarbon receptor attenuates fibroblast growth factor 21 expression","volume":"291","author":"Girer","year":"2016","journal-title":"J. Biol. Chem."},{"key":"2026080520363606300_ref51","doi-asserted-by":"crossref","first-page":"36401","DOI":"10.1074\/jbc.M110.172866","article-title":"Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding","volume":"285","author":"Tong","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026080520363606300_ref52","doi-asserted-by":"crossref","first-page":"14254","DOI":"10.1096\/fj.201901347RR","article-title":"KLF15-activating Twist2 ameliorated hepatic steatosis by inhibiting inflammation and improving mitochondrial dysfunction via NF-kappaB-FGF21 or SREBP1c-FGF21 pathway","volume":"33","author":"Zhou","year":"2019","journal-title":"FASEB J."},{"key":"2026080520363606300_ref53","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.jnutbio.2011.03.023","article-title":"Liver X receptor negatively regulates fibroblast growth factor 21 in the fatty liver induced by cholesterol-enriched diet","volume":"23","author":"Uebanso","year":"2012","journal-title":"J. Nutr. Biochem."},{"key":"2026080520363606300_ref54","doi-asserted-by":"crossref","first-page":"46230","DOI":"10.1038\/srep46230","article-title":"Transgenic mouse model for imaging of ATF4 translational activation-related cellular stress responses in vivo","volume":"7","author":"Iwawaki","year":"2017","journal-title":"Sci. Rep."},{"key":"2026080520363606300_ref55","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.molcel.2018.01.019","article-title":"N(6)-methyladenosine guides mRNA alternative translation during integrated stress response","volume":"69","author":"Zhou","year":"2018","journal-title":"Mol. Cell"},{"key":"2026080520363606300_ref56","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/s41467-017-02488-y","article-title":"GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose","volume":"9","author":"Iwasaki","year":"2018","journal-title":"Nat. Commun."},{"key":"2026080520363606300_ref57","first-page":"1065","article-title":"Safety and efficacy of D-tagatose in glycemic control in subjects with type 2 diabetes","volume":"3","author":"Ensor","year":"2015","journal-title":"J. Endocrinol. Diabetes Obes."},{"key":"2026080520363606300_ref58","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/s42003-025-08391-3","article-title":"Gut microbial utilization of the alternative sweetener, D-allulose, via AlsE","volume":"8","author":"Minabou Ndjite","year":"2025","journal-title":"Commun. Biol."}],"container-title":["The Journal of Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jb\/advance-article-pdf\/doi\/10.1093\/jb\/mvag059\/70165783\/mvag059.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jb\/advance-article-pdf\/doi\/10.1093\/jb\/mvag059\/70165783\/mvag059.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:36:51Z","timestamp":1785976611000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jb\/advance-article\/doi\/10.1093\/jb\/mvag059\/8742365"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":58,"URL":"https:\/\/doi.org\/10.1093\/jb\/mvag059","relation":{},"ISSN":["0021-924X","1756-2651"],"issn-type":[{"value":"0021-924X","type":"print"},{"value":"1756-2651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]},"article-number":"mvag059"}}