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Necroptosis, an inflammatory cell death pathway, is elevated in MAFLD patients and mouse models, yet its role is unclear due to the diverse mouse models and inhibition strategies. In our study, we inhibited necroptosis by targeting mixed lineage kinase domain-like pseudokinase (MLKL), the terminal effector of necroptosis, in a high-fat, high-fructose, high-cholesterol (HFHFrHC) mouse model of diet-induced MAFLD. Despite the HFHFrHC diet upregulating MLKL (2.5-fold), WT mice livers showed no increase in necroptosis markers or associated proinflammatory cytokines. Surprisingly, Mlkl\u2212\/\u2212 mice experienced exacerbated liver inflammation without protection from diet-induced liver damage, steatosis, or fibrosis. In contrast, Mlkl+\/\u2212 mice showed a significant reduction in these parameters that was associated with elevated Ppar\u03b1 and Ppar\u03b3 levels. Both Mlkl\u2212\/\u2212 and Mlkl+\/\u2212 mice on the HFHFrHC diet resisted diet-induced obesity, attributed to the increased beiging, enhanced oxygen consumption, and energy expenditure due to adipose tissue, and exhibited improved insulin sensitivity. These findings highlight the tissue-specific effects of MLKL on the liver and adipose tissue, and they suggest a dose-dependent effect of MLKL on liver pathology.<\/jats:p>","DOI":"10.3390\/ijms25052813","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T02:59:39Z","timestamp":1709175579000},"page":"2813","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Non-Necroptotic Roles of MLKL in Diet-Induced Obesity, Liver Pathology, and Insulin Sensitivity: Insights from a High-Fat, High-Fructose, High-Cholesterol Diet Mouse Model"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1728-4818","authenticated-orcid":false,"given":"Phoebe","family":"Ohene-Marfo","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7290-4728","authenticated-orcid":false,"given":"Hoang Van M.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabira","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2168-8337","authenticated-orcid":false,"given":"Nidheesh","family":"Thadathil","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan H.","family":"Nicklas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0017-5158","authenticated-orcid":false,"given":"Dawei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramasamy","family":"Selvarani","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2274-7706","authenticated-orcid":false,"given":"Jacob W.","family":"Farriester","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Varshney","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kinter","sequence":"additional","affiliation":[{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlan","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Oklahoma Center for Geroscience & Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Oklahoma City VA Medical Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6147-212X","authenticated-orcid":false,"given":"Michael C.","family":"Rudolph","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3669-4820","authenticated-orcid":false,"given":"Sathyaseelan S.","family":"Deepa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"},{"name":"Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kitade, H., Chen, G., Ni, Y., and Ota, T. 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