{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T16:27:27Z","timestamp":1782232047286,"version":"3.54.5"},"reference-count":35,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T00:00:00Z","timestamp":1770681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002241","name":"JST FOREST Program","doi-asserted-by":"publisher","award":["JPMJFR225C"],"award-info":[{"award-number":["JPMJFR225C"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Grant-in-Aid for Exploratory Research JSPS KAKENHI","doi-asserted-by":"publisher","award":["24K22258"],"award-info":[{"award-number":["24K22258"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Grant-in-Aid for Scientific Research (B) JSPS KAKENHI","doi-asserted-by":"publisher","award":["25K03073"],"award-info":[{"award-number":["25K03073"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012036","name":"Lotte Research Promotion","doi-asserted-by":"crossref","award":["2023A2003"],"award-info":[{"award-number":["2023A2003"]}],"id":[{"id":"10.13039\/501100012036","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Obesity is characterized by dysregulated hypothalamic energy homeostasis and reduced central responsiveness to the anorexigenic hormones leptin and insulin. \u03b2-Hydroxybutyrate (\u03b2-HB), a major ketone body, has recently garnered attention as a signaling metabolite. However, its effects on hypothalamic leptin and insulin responsiveness remain unclear. This study aimed to investigate the effects of \u03b2-HB on hypothalamic hormone responsiveness and the associated molecular mechanisms, primarily using a high-fat diet (HFD)-induced obese mouse model. Methods: Male mice were fed an HFD to induce obesity and treated with \u03b2-HB via oral or intracerebroventricular (ICV) administration. Feeding behavior following leptin and insulin administration was evaluated, and activation of hypothalamic leptin-induced STAT3 signaling and insulin-induced Akt signaling was analyzed. In addition, mRNA expression of inflammation-related and appetite-regulating genes was assessed by quantitative PCR. Normal mice also received chronic ICV administration of \u03b2-HB from the onset of HFD feeding, and changes in body weight and cumulative food intake were measured. Results: Both oral and ICV administration of \u03b2-HB significantly enhanced the anorexigenic responses to leptin and insulin in HFD-induced obese mice. At the molecular level, leptin-induced STAT3 phosphorylation and insulin-induced Akt phosphorylation were enhanced in the hypothalamus. Gene expression analysis revealed reduced SOCS3 and TNF\u03b1 expression and increased POMC expression. Furthermore, chronic ICV administration of \u03b2-HB from the onset of HFD feeding significantly suppressed body weight gain and the increase in cumulative food intake. Conclusions: This study demonstrates that \u03b2-HB improves hypothalamic leptin and insulin responsiveness in obese mice and modulates the associated molecular environment. These findings suggest that \u03b2-HB acts as a metabolically responsive signaling molecule regulating hypothalamic function, providing a basis for novel metabolic intervention strategies against obesity.<\/jats:p>","DOI":"10.3390\/nu18040582","type":"journal-article","created":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T15:23:14Z","timestamp":1770736994000},"page":"582","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Ketone Body \u03b2-Hydroxybutyrate Enhances Hypothalamic Leptin and Insulin Responsiveness"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4054-8128","authenticated-orcid":false,"given":"Ran","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Agricultural Chemistry, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki-shi 214-8571, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nozomi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Agricultural Chemistry, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki-shi 214-8571, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5003-2460","authenticated-orcid":false,"given":"Kentaro","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Agricultural Chemistry, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki-shi 214-8571, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,10]]},"reference":[{"key":"ref_1","unstructured":"(2025, December 14). Obesity and Overweight. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/obesity-and-overweight."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41574-019-0176-8","article-title":"Obesity: Global Epidemiology and Pathogenesis","volume":"15","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Guh, D.P., Zhang, W., Bansback, N., Amarsi, Z., Birmingham, C.L., and Anis, A.H. (2009). The Incidence of Co-Morbidities Related to Obesity and Overweight: A Systematic Review and Meta-Analysis. BMC Public Health, 9.","DOI":"10.1186\/1471-2458-9-88"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/nature05026","article-title":"Central Nervous System Control of Food Intake and Body Weight","volume":"443","author":"Morton","year":"2006","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/35007534","article-title":"Central Nervous System Control of Food Intake","volume":"404","author":"Schwartz","year":"2000","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/nn1455","article-title":"Anatomy and Regulation of the Central Melanocortin System","volume":"8","author":"Cone","year":"2005","journal-title":"Nat. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1038\/nm1295-1311","article-title":"Leptin Levels Reflect Body Lipid Content in Mice: Evidence for Diet-Induced Resistance to Leptin Action","volume":"1","author":"Frederich","year":"1995","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/S0306-4522(01)00142-7","article-title":"Hypothalamic Leptin Resistance Is Associated with Impaired Leptin Signal Transduction in Aged Obese Rats","volume":"104","author":"Scarpace","year":"2001","journal-title":"Neuroscience"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.2337\/diab.46.11.1782","article-title":"Inhibition of Food Response to Intracerebroventricular Injection of Leptin Is Attenuated in Rats with Diet-Induced Obesity","volume":"46","author":"Widdowson","year":"1997","journal-title":"Diabetes"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1172\/JCI9842","article-title":"Two Defects Contribute to Hypothalamic Leptin Resistance in Mice with Diet-Induced Obesity","volume":"105","author":"Pierroz","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1172\/JCI105650","article-title":"Brain Metabolism during Fasting","volume":"46","author":"Owen","year":"1967","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1126\/science.1227166","article-title":"Suppression of Oxidative Stress by \u03b2-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor","volume":"339","author":"Shimazu","year":"2013","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nm.3804","article-title":"The ketone metabolite \u03b2-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease","volume":"21","author":"Youm","year":"2015","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1016\/j.celrep.2016.08.039","article-title":"Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions","volume":"16","author":"Kaneko","year":"2016","journal-title":"Cell Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev-nutr-071816-064916","article-title":"\u03b2-Hydroxybutyrate","volume":"37","author":"Newman","year":"2017","journal-title":"Annu. Rev. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.cmet.2016.12.022","article-title":"Multi-Dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics","volume":"25","author":"Puchalska","year":"2017","journal-title":"Cell Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1038\/nature01388","article-title":"STAT3 Signalling Is Required for Leptin Regulation of Energy Balance but Not Reproduction","volume":"421","author":"Bates","year":"2003","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4661","DOI":"10.1073\/pnas.0303992101","article-title":"Disruption of Neural Signal Transducer and Activator of Transcription 3 Causes Obesity, Diabetes, Infertility, and Thermal Dysregulation","volume":"101","author":"Gao","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1210\/en.2007-1307","article-title":"Hypothalamic Phosphatidylinositol 3-Kinase Pathway of Leptin Signaling Is Impaired during the Development of Diet-Induced Obesity in FVB\/N Mice","volume":"149","author":"Metlakunta","year":"2008","journal-title":"Endocrinology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/ng0996-95","article-title":"Leptin Activation of Stat3 in the Hypothalamus of Wild-Type and Ob\/Ob Mice but Not Db\/Db Mice","volume":"14","author":"Vaisse","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"227","DOI":"10.2337\/diabetes.52.2.227","article-title":"Insulin Activation of Phosphatidylinositol 3-Kinase in the Hypothalamic Arcuate Nucleus: A Key Mediator of Insulin-Induced Anorexia","volume":"52","author":"Niswender","year":"2003","journal-title":"Diabetes"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Thon, M., Hosoi, T., and Ozawa, K. (2016). Possible Integrative Actions of Leptin and Insulin Signaling in the Hypothalamus Targeting Energy Homeostasis. Front. Endocrinol., 7.","DOI":"10.3389\/fendo.2016.00138"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.fob.2013.09.002","article-title":"Diet-Induced Obesity Induces Endoplasmic Reticulum Stress and Insulin Resistance in the Amygdala of Rats","volume":"3","author":"Castro","year":"2013","journal-title":"FEBS Open Bio"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/S1097-2765(00)80062-3","article-title":"Identification of SOCS-3 as a Potential Mediator of Central Leptin Resistance","volume":"1","author":"Elmquist","year":"1998","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/nm1071","article-title":"Socs3 Deficiency in the Brain Elevates Leptin Sensitivity and Confers Resistance to Diet-Induced Obesity","volume":"10","author":"Mori","year":"2004","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.1210\/en.2016-1038","article-title":"Changes in Leptin Signaling by SOCS3 Modulate Fasting-Induced Hyperphagia and Weight Regain in Mice","volume":"157","author":"Pedroso","year":"2016","journal-title":"Endocrinology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12986-021-00569-w","article-title":"STAT3 Phosphorylation in Central Leptin Resistance","volume":"18","author":"Liu","year":"2021","journal-title":"Nutr. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1172\/JCI88878","article-title":"Hypothalamic Inflammation in Obesity and Metabolic Disease","volume":"127","author":"Jais","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"983401","DOI":"10.1155\/2014\/983401","article-title":"BHBA Suppresses LPS-Induced Inflammation in BV-2 Cells by Inhibiting NF-\u03baB Activation","volume":"2014","author":"Fu","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1167\/iovs.11-8447","article-title":"GPR109A as an Anti-Inflammatory Receptor in Retinal Pigment Epithelial Cells and Its Relevance to Diabetic Retinopathy","volume":"53","author":"Gambhir","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.cmet.2010.03.002","article-title":"Direct Insulin and Leptin Action in Pro-Opiomelanocortin Neurons Is Required for Normal Glucose Homeostasis and Fertility","volume":"11","author":"Hill","year":"2010","journal-title":"Cell Metab."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liu, Z., Xiao, T., and Liu, H. (2023). Leptin Signaling and Its Central Role in Energy Homeostasis. Front. Neurosci., 17.","DOI":"10.3389\/fnins.2023.1238528"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12974-014-0230-3","article-title":"Anti-Inflammatory Effects of BHBA in Both in Vivo and in Vitro Parkinson\u2019s Disease Models Are Mediated by GPR109A-Dependent Mechanisms","volume":"12","author":"Fu","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jayashankar, S.S., Tajul Arifin, K., and Nasaruddin, M.L. (2023). \u03b2-Hydroxybutyrate Regulates Activated Microglia to Alleviate Neurodegenerative Processes in Neurological Diseases: A Scoping Review. Nutrients, 15.","DOI":"10.3390\/nu15030524"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Cuenoud, B., Hartweg, M., Godin, J.-P., Croteau, E., Maltais, M., Castellano, C.-A., Carpentier, A.C., and Cunnane, S.C. (2020). Metabolism of Exogenous D-Beta-Hydroxybutyrate, an Energy Substrate Avidly Consumed by the Heart and Kidney. Front. Nutr., 7.","DOI":"10.3389\/fnut.2020.00013"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/4\/582\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T05:14:15Z","timestamp":1770873255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/4\/582"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,10]]},"references-count":35,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["nu18040582"],"URL":"https:\/\/doi.org\/10.3390\/nu18040582","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,10]]}}}