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The expansion of adipose tissues in obesity induces insulin resistance and low-grade systemic inflammation, promoting kidney damage. Our previous studies have demonstrated that agomelatine (AGOM) exerts renoprotective effects in experimental models of obesity and insulin resistance through various mechanisms, including the attenuation of ER stress and oxidative stress. This study aimed to further explore the effects of agomelatine on renal inflammation, insulin signaling, and necroptosis in obese, insulin-resistant rats. Obesity was induced in rats with a high-fat diet for 16 weeks, followed by 4 weeks of treatment with 20 mg kg\u22121 day\u22121 of AGOM or 10 mg kg\u22121 day\u22121 of pioglitazone (PIO). The results showed that insulin resistance was improved after treatment with AGOM and PIO, as demonstrated by the reduction in fasting plasma glucose, insulin, and HOMA-IR. Both treatments restored the levels of renal insulin signaling proteins. Moreover, AGOM inhibited TNF\u03b1, TNFR1, NF-\u0138B, COX2, and IL1\u03b2, which attenuated the necroptosis-related proteins RIPK3 and MLKL. AGOM also prevented kidney DNA fragmentation, as detected by the TUNEL assay. In an obese condition, the level of the tight junction protein claudin-1 (CLDN1) was enhanced after being treated with AGOM. In conclusion, the novel mechanisms associated with AGOM and involved in limiting kidney injury were the inhibition of the TNF\u03b1\/NF-\u0138B\/p-RIPK3 pathway and a reduction in inflammation and necroptosis. This suggested that AGOM could be an effective treatment for inhibiting kidney dysfunction in cases of obesity and insulin resistance. These findings open new avenues for the management of renal dysfunction, with implications for personalized medicine.<\/jats:p>","DOI":"10.3390\/ijms26051940","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T06:47:17Z","timestamp":1740379637000},"page":"1940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Agomelatine Mitigates Kidney Damage in Obese Insulin-Resistant Rats by Inhibiting Inflammation and Necroptosis via the TNF-\u03b1\/NF-\u0138B\/p-RIPK3 Pathway"],"prefix":"10.3390","volume":"26","author":[{"given":"Sasivimon","family":"Promsan","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Chiang Mai University, Intravaroros Road, Chiang Mai 50200, Thailand"},{"name":"Division of Physiology, School of Medical Science, University of Phayao, Phayao 56000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nattavadee","family":"Pengrattanachot","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Chiang Mai University, Intravaroros Road, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2221-9826","authenticated-orcid":false,"given":"Nichakorn","family":"Phengpol","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Chiang Mai University, Intravaroros Road, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prempree","family":"Sutthasupha","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Chiang Mai University, Intravaroros Road, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"La-ongdao","family":"Thongnak","sequence":"additional","affiliation":[{"name":"Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok 10210, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5087-680X","authenticated-orcid":false,"given":"Krit","family":"Jaikumkao","sequence":"additional","affiliation":[{"name":"Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4522-0026","authenticated-orcid":false,"given":"Anusorn","family":"Lungkaphin","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine, Chiang Mai University, Intravaroros Road, Chiang Mai 50200, Thailand"},{"name":"Functional Foods for Health and Disease, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand"},{"name":"Functional Food Research Center for Well-Being, Multidisciplinary Research Institute, Chiang Mai University, Chiang Mai 50200, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3288","DOI":"10.1093\/ndt\/gfp302","article-title":"Saturated fatty acids induce insulin resistance in human podocytes: Implications for diabetic nephropathy","volume":"24","author":"Lennon","year":"2009","journal-title":"Nephrol. 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