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Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model.<\/jats:p>","DOI":"10.1083\/jcb.202405175","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T02:20:56Z","timestamp":1719541256000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Integrated stress response activator halofuginone protects mice from diabetes-like phenotypes"],"prefix":"10.1083","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8296-2059","authenticated-orcid":true,"given":"Shashank","family":"Rai","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00tw3jy02","id-type":"ROR","asserted-by":"publisher"}],"name":"MRC Laboratory of Molecular Biology 1 , Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1673-1855","authenticated-orcid":true,"given":"Maria","family":"Szaruga","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00tw3jy02","id-type":"ROR","asserted-by":"publisher"}],"name":"MRC Laboratory of Molecular Biology 1 , Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7004-1615","authenticated-orcid":true,"given":"Aleksandra P.","family":"Pitera","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00tw3jy02","id-type":"ROR","asserted-by":"publisher"}],"name":"MRC Laboratory of Molecular Biology 1 , Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9185-0558","authenticated-orcid":true,"given":"Anne","family":"Bertolotti","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00tw3jy02","id-type":"ROR","asserted-by":"publisher"}],"name":"MRC Laboratory of Molecular Biology 1 , Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2024,8,16]]},"reference":[{"key":"2024081613212997700_bib1","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1158\/0008-5472.CAN-12-3109","article-title":"Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity","volume":"73","author":"Atkins","year":"2013","journal-title":"Cancer Res."},{"key":"2024081613212997700_bib2","doi-asserted-by":"publisher","DOI":"10.3791\/51779","article-title":"RNA Isolation from mouse pancreas: A ribonuclease-rich tissue","author":"Azevedo-Pouly","year":"2014","journal-title":"J. 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