{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T20:29:55Z","timestamp":1788812995214,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:00:00Z","timestamp":1771804800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["25K10163"],"award-info":[{"award-number":["25K10163"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"name":"COMIT Collaborative Research 2024"},{"name":"Japan Association for Diabetes Education and Care (JADEC) 2024"},{"name":"Matsutani Chemical Industry Co."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Rare sugar D-Allulose, a zero-calorie sweetener, markedly ameliorates obesity. It reportedly stimulates the release of endogenous glucagon-like peptide 1 (GLP-1) to activate vagal afferent and directly influences the neurons in hypothalamic arcuate nucleus (ARH), thus evoking vagal and central nervous routes. D-Allulose can now be produced substantially, being expected for diet therapy. Oral form GLP-1 receptor agonist (GLP-1RA), Oral semaglutide (O-Sema), without injection markedly ameliorates obesity. It evokes only central nervous route. Thus, these GLP-1-based substances utilize common\/distinct routes, suggesting common\/distinct effects on obesity and related disorders including sarcopenia. To address it, this study precisely compared their effects. Methods: O-Sema and D-Allulose were administered to diet-induced obese mice under identical conditions, equivalent doses, oral gavage, and food\/water deprivation. Acute and sub-chronic effects on food intake, body weight and grip strength were measured. Results: Acutely, D-Allulose rapidly and O-Sema slowly reduced feeding. Sub-chronically, D-Allulose and O-Sema profoundly reduced food intake and weight in the early period (0\u20133 days) of treatment. The weight loss was diminished with O-Sema but maintained with D-Allulose in the late period (4\u201310 days) and after termination of treatment. D-Allulose and O-Sema increased muscle strength. Mechanistically, D-Allulose and semaglutide similarly activated anorexigenic leptin-responsive neurons while only D-Allulose significantly inhibited orexigenic ghrelin-responsive neurons in ARH. Conclusions: D-Allulose and O-Sema equally elicit weight reduction possibly via the central nervous route including ARH anorexigenic neuron activation. The weight loss is rebounded with O-Sema, while it is maintained with D-Allulose possibly via combined vagal afferent and central nervous routes including ARH orexigenic neuron inhibition. Their optimal use potentially provides precise control of obesity and related disorders.<\/jats:p>","DOI":"10.3390\/nu18040707","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T14:05:11Z","timestamp":1771855511000},"page":"707","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["D-Allulose Reduces Weight More Persistently than Oral Semaglutide While Both Equally Elevate Grip Strength in Diet-Induced Obese Mice"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1233-0392","authenticated-orcid":false,"given":"Yermek","family":"Rakhat","sequence":"first","affiliation":[{"name":"Division of Integrative Physiology, Center for Integrative Physiology, Kansai Electric Power Medical Research Institute, Osaka 553-0003, Japan"},{"name":"Department of Diabetes, Endocrinology and Metabolism\/Rheumatology and Clinical Immunology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7345-7974","authenticated-orcid":false,"given":"Seiya","family":"Banno","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolism\/Rheumatology and Clinical Immunology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4102-7229","authenticated-orcid":false,"given":"Dauren","family":"Zhantleu","sequence":"additional","affiliation":[{"name":"Division of Integrative Physiology, Center for Integrative Physiology, Kansai Electric Power Medical Research Institute, Osaka 553-0003, Japan"},{"name":"Department of Diabetes, Endocrinology and Metabolism\/Rheumatology and Clinical Immunology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Tsunekawa","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolism\/Rheumatology and Clinical Immunology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5334-7687","authenticated-orcid":false,"given":"Daisuke","family":"Yabe","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology and Metabolism\/Rheumatology and Clinical Immunology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"},{"name":"Departments of Diabetes Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan"},{"name":"Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Osaka 553-0003, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Seino","sequence":"additional","affiliation":[{"name":"Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Osaka 553-0003, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0655-4384","authenticated-orcid":false,"given":"Yusaku","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Functional Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4160-2652","authenticated-orcid":false,"given":"Toshihiko","family":"Yada","sequence":"additional","affiliation":[{"name":"Division of Integrative Physiology, Center for Integrative Physiology, Kansai Electric Power Medical Research Institute, Osaka 553-0003, Japan"},{"name":"Department of Diabetes, Endocrinology and Metabolism\/Rheumatology and Clinical Immunology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan"},{"name":"Center for One Medicine Innovative Translational Research, Gifu University Institute for Advanced Study, Gifu 501-1194, Japan"},{"name":"Department of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Aichi 470-1192, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.pcad.2022.11.013","article-title":"Updates on obesity and the obesity paradox in cardiovascular diseases","volume":"78","author":"Tutor","year":"2023","journal-title":"Prog. 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