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Pioglitazone (PGZ), a thiazolidinedione (TZD) that acts via peroxisome proliferator activated receptor gamma (PPAR<jats:italic>\u03b3<\/jats:italic>) is the only agent that has shown consistent benefit and efficacy in clinical trials. However, the mechanism of its therapeutic effect on NAFLD remains unclear. The poor understanding may be due to problems with mouse, a species most used for animal experiments. TZDs exacerbate fatty liver in mouse models while they improve it in rat models like in human patients. Therefore, we compared the effects of TZDs including PGZ and rosiglitazone (RGZ) in <jats:italic>ob\/ob<\/jats:italic> mice and <jats:italic>Lep<\/jats:italic><jats:sup><jats:italic>mkyo<\/jats:italic><\/jats:sup><jats:italic>\/Lep<\/jats:italic><jats:sup><jats:italic>mkyo<\/jats:italic><\/jats:sup> rats, models of leptin-deficient obesity, and A-ZIP\/F-1 mice and seipin knockout (SKO) rats, models of generalized lipodystrophy. <jats:italic>Pparg<\/jats:italic> mRNA expression was markedly upregulated in fatty livers of mouse models while it was unchanged in rat models. TZDs exacerbated fatty liver in <jats:italic>ob\/ob<\/jats:italic> and A-ZIP\/F-1 mice, improved it in <jats:italic>Lep<\/jats:italic><jats:sup><jats:italic>mkyo<\/jats:italic><\/jats:sup><jats:italic>\/Lep<\/jats:italic><jats:sup><jats:italic>mkyo<\/jats:italic><\/jats:sup> rats and showed no effect in SKO rats. Gene expression analyses of <jats:italic>Pparg<\/jats:italic> and its target gene, Fsp27 revealed that PPAR<jats:italic>\u03b3<\/jats:italic> in the adipose tissue is the exclusive therapeutic target of TZDs in rats but PPAR<jats:italic>\u03b3<\/jats:italic> in the liver in addition to the adipose tissue is also a major site of actions for TZDs in mice. Although the response to TZDs in mice is the complete opposite of that in human patients, no report has pointed out the problem with TZD studies using mouse models so far. The present study might provide useful suggestions in research on TZDs.<\/jats:p>","DOI":"10.1038\/s41598-021-04036-7","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T11:04:32Z","timestamp":1641812672000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Different sites of actions make different responses to thiazolidinediones between mouse and rat models of fatty liver"],"prefix":"10.1038","volume":"12","author":[{"given":"Chihiro","family":"Ebihara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Aizawa-Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentino","family":"Gumbilai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Ebihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,10]]},"reference":[{"key":"4036_CR1","doi-asserted-by":"crossref","unstructured":"Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). 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