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The complex molecular underpinnings of how lipid overload and lipid metabolites lead to the deregulation of metabolic processes are incompletely understood. We assessed hepatic post\u2010translational alterations in response to treatment of cells with saturated and unsaturated free fatty acids and the consumption of a high\u2010fat diet by mice. These data revealed widespread tyrosine phosphorylation changes affecting a large number of enzymes involved in metabolic processes as well as canonical receptor\u2010mediated signal transduction networks. Targeting two of the most prominently affected molecular features in our data, SRC\u2010family kinase activity and elevated reactive oxygen species, significantly abrogated the effects of saturated fat exposure\n                    <jats:italic>in\u00a0vitro<\/jats:italic>\n                    and high\u2010fat diet\n                    <jats:italic>in\u00a0vivo<\/jats:italic>\n                    . In summary, we present a comprehensive view of diet\u2010induced alterations of tyrosine signaling networks, including proteins involved in fundamental metabolic pathways.\n                  <\/jats:p>","DOI":"10.15252\/msb.20198849","type":"journal-article","created":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T11:29:48Z","timestamp":1564658988000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["High\u2010fat diet in a mouse insulin\u2010resistant model induces widespread rewiring of the phosphotyrosine signaling network"],"prefix":"10.1038","volume":"15","author":[{"given":"Antje","family":"Dittmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman J","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina L","family":"Soltero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nader","family":"Morshed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyeko D","family":"Mana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6mer H","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0130-1652","authenticated-orcid":false,"given":"Roger J","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1545-1651","authenticated-orcid":false,"given":"Forest M","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,1]]},"reference":[{"key":"BFMSB198849_CR1","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/emboj\/18.5.1321","volume":"18","author":"V Adler","year":"1999","unstructured":"Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR et\u00a0al (1999) Regulation of JNK signaling by GSTp. 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