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We aimed to investigate the effects of peripheral DIOs on thyroid hormone economy independent of the hypothalamus\u2010pituitary\u2010thyroid axis. We cloned coding sequences of human DIOs with FLAG\u2010tag and HiBiT\u2010tag sequences into a pcDNA3.1 vector. To obtain full\u2010length proteins, we modified these vectors by cloning the selenocysteine insertion sequence of each DIO (SECIS vectors). Western blot analyses and HiBiT lytic assay using HEK293T cells revealed that SECIS vectors expressed full\u2010length proteins with substantial activity. Subsequently, in vivo transfections of pLIVE\u2010based SECIS vectors into male C57BL\/6J mice were performed by hydrodynamic gene delivery to generate mice overexpressing DIOs predominantly in the liver (D1, D2, and D3\u00a0mice). After 7\u00a0days from transfections, mice were analyzed to clarify phenotypes. To summarize, serum thyroid hormone levels did not change in D1\u00a0mice but D2\u00a0mice had higher serum free T3\u00a0levels. D3\u00a0mice developed hypothyroidism with higher serum reverse T3 (rT3) levels. Transfections with levothyroxine administration suggested that thyroid hormone action was upregulated in D2\u00a0mice. Our DIO\u2010overexpressing mice provided insights on the physiological properties of upregulated DIOs: D2 augments local thyroid hormone action and recruits T3 into the circulation: D3 decreases circulating T3 and T4\u00a0levels with elevated rT3, leading to consumptive hypothyroidism. As D3\u00a0mice are expected to be a novel hypothyroidism model, they can contribute to progress in the field of thyroid hormone economy and action.<\/jats:p>","DOI":"10.1096\/fj.202101288rr","type":"journal-article","created":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T01:29:55Z","timestamp":1641259795000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Thyroid hormone economy in mice overexpressing iodothyronine deiodinases"],"prefix":"10.1096","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-502X","authenticated-orcid":false,"given":"Ichiro","family":"Yamauchi","sequence":"first","affiliation":[{"name":"Department of Diabetes, Endocrinology and Nutrition Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoriko","family":"Sakane","sequence":"additional","affiliation":[{"name":"Department of Diabetes, Endocrinology 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