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Here we explore the variation in macronutrient tolerance in <jats:italic>Drosophila melanogaster<\/jats:italic> using the <jats:italic>Drosophila<\/jats:italic> genetic reference panel, a collection of ~200 strains derived from a single natural population. Our study demonstrates that <jats:italic>D. melanogaster<\/jats:italic>, often considered a \u201cdietary generalist\u201d, displays marked genetic variation in survival on different diets, notably on high-sugar diet. Our genetic analysis and functional validation identify several regulators of macronutrient tolerance, including <jats:italic>CG10960\/GLUT8<\/jats:italic>, <jats:italic>Pkn<\/jats:italic> and <jats:italic>Eip75B<\/jats:italic>. We also demonstrate a role for the JNK pathway in sugar tolerance and de novo lipogenesis. Finally, we report a role for <jats:italic>tailles<\/jats:italic>s, a conserved orphan nuclear hormone receptor, in regulating sugar metabolism via insulin-like peptide secretion and sugar-responsive <jats:italic>CCHamide-2<\/jats:italic> expression. Our study provides support for the use of nutrigenomics in the development of personalized nutrition.<\/jats:p>","DOI":"10.1038\/s41467-022-29183-x","type":"journal-article","created":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T10:22:53Z","timestamp":1648462973000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Genetic variation of macronutrient tolerance in Drosophila melanogaster"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9253-5816","authenticated-orcid":false,"given":"E.","family":"Havula","sequence":"first","affiliation":[]},{"given":"S.","family":"Ghazanfar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1746-0332","authenticated-orcid":false,"given":"N.","family":"Lamichane","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4158-1521","authenticated-orcid":false,"given":"D.","family":"Francis","sequence":"additional","affiliation":[]},{"given":"K.","family":"Hasygar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6419-1980","authenticated-orcid":false,"given":"Y.","family":"Liu","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4236-2494","authenticated-orcid":false,"given":"L. 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