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Leflunomide treatment in rheumatoid arthritis (RA) patients has been associated with weight loss and decreased blood glucose levels, which cannot be attributed to its known side effects. Our prior studies showed that A77 1726, the active metabolite of leflunomide, acts as an inhibitor of S6K1 to sensitize the insulin receptor and control hyperglycemia. Whether the anti\u2010obesity effect of leflunomide is mediated by targeting S6K1 and its underlying mechanisms remain unclear. Here, we report that A77 1726 induced LC3 lipidation and increased the formation of autophagosomes and lipoautolysosomes in 3T3\u2010L1 adipocytes by activating TGF\u2010\u03b2\u2010activated kinase 1 (TAK1), AMP\u2010activated kinase (AMPK), and Unc\u201051 like autophagy\u2010activated kinase 1 (ULK1). A77 1726 reduced the content of lipid droplets in 3T3\u2010L1 adipocytes, which was blocked by bafilomycin or by beclin\u20101 knockdown. Similar observations were made in murine adipocytes differentiated from S6K1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    embryonic fibroblasts (MEFs). Leflunomide treatment restricted bodyweight gains in\n                    <jats:italic>ob\/ob<\/jats:italic>\n                    mice and reduced the visceral fat deposit and the size of adipocytes. Leflunomide treatment induced autophagy in adipose and liver tissues and reduced hepatic lipid contents. Consistently, S6K1 knockout increased the levels of LC3 lipidation in the liver, muscle, and fat of S6K\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Leflunomide treatment and S6K1 deficiency both induced TAK1, AMPK, and ULK1 phosphorylation in these tissues. These observations collectively suggest that leflunomide controls obesity in part by activating AMPK and inducing lipophagy. Our study provides insights into the mechanisms of leflunomide\u2010mediated anti\u2010obesity activity.\n                  <\/jats:p>","DOI":"10.1096\/fj.202301162r","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T13:19:09Z","timestamp":1696425549000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Leflunomide alleviates obesity via activation of the\n                    <scp>TAK1\u2010AMPK<\/scp>\n                    pathway and induction of lipophagy"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7036-6634","authenticated-orcid":false,"given":"Xiaoyue","family":"Ji","sequence":"first","affiliation":[{"name":"Institute of Comparative Medicine, College of Veterinary Medicine Yangzhou University  Yangzhou China"},{"name":"Joint International Research Laboratory of Agriculture and Agri\u2010Product Safety of Ministry of Education of China  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1578-4667","authenticated-orcid":false,"given":"Junhong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Animal Science and Food Engineering Jinling Institute of Technology  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9479-687X","authenticated-orcid":false,"given":"Chaoying","family":"You","sequence":"additional","affiliation":[{"name":"Institute of Comparative Medicine, College of Veterinary Medicine Yangzhou University  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7254-454X","authenticated-orcid":false,"given":"Jing","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Comparative Medicine, College of Veterinary Medicine Yangzhou University  Yangzhou 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