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However, FGF-21 levels are paradoxically higher in obesity, indicating a hormone-resistant state that may hinder the benefits of SGLT2i.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>To define if a different energy status influences the response to SGLT2i, we evaluated the effects of dapagliflozin administration on nine-week-old C57BL\/6J wild-type and B6.V-LEP <jats:italic>ob<\/jats:italic>\/<jats:italic>ob<\/jats:italic> mice as a model of genetic obesity. Blood glucose, body weight and food intake were evaluated, and the FGF-21 expression was determined in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and brown adipose tissue (BAT). In the liver, FGF-21 gene expression, protein concentration and triglyceride content were evaluated.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>glucose plasma levels and body weight were higher in <jats:italic>ob<\/jats:italic>\/<jats:italic>ob<\/jats:italic> than in lean mice. After four weeks of treatment, dapagliflozin reduced blood glucose levels and body weight in both animal models, but weight loss was more significant in lean mice. The baseline expression of FGF-21 was higher in both SAT, VAT and the liver of <jats:italic>ob<\/jats:italic>\/<jats:italic>ob<\/jats:italic> mice, whereas it was almost undetectable in BAT in both animal groups. After the treatment period, dapagliflozin was shown to increase FGF-21 expression in VAT only in lean animals, while the expression was unaffected in <jats:italic>ob<\/jats:italic>\/<jats:italic>ob<\/jats:italic> mice. Similar effects were observed in the liver analyses, along with no variation in triglyceride content.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>SGLT2i administration results in less pronounced metabolic effects in <jats:italic>ob<\/jats:italic>\/<jats:italic>ob<\/jats:italic> mice than in lean mice. This data suggests a less sensitive response in obesity, probably due to a chronic stimulation leading to abnormalities of the SGLT2i-FGF-21 axis which should be considered in managing patients affected by genetic obesity.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12902-025-01879-3","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T03:56:16Z","timestamp":1741578976000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The effects of SGLT2 inhibitors on metabolic phenotype and FGF-21 expression from the adipose tissue and the liver are less pronounced in ob\/ob mice"],"prefix":"10.1186","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7678-5671","authenticated-orcid":false,"given":"Angelo","family":"Di Vincenzo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marnie","family":"Granzotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Crescenzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Fioretto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Vettor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Rossato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,10]]},"reference":[{"key":"1879_CR1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107038","author":"SD Anker","year":"2021","unstructured":"Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, B\u00f6hm M, et al. 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All the procedures involving animal care followed institutional guidelines (European Economic Community Council Directive 86\/609, OJ L 358, 1 Dec.2012, 1987; NIH Guide for the Care and Use of Laboratory Animals, NIH Publication no. 85\u201323, 1985).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"P.F. is involved as an advisory board member and speaker for: AstraZeneca, Eli Lilly, Boehringer Ingelheim, Novo, and Bayer. The other authors declare that they have no competing interests with this research.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"63"}}