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While caspase\u20106, an executioner caspase, is known for its role in neurodegeneration and cell death, its broader physiological functions remain poorly understood. Our previous study revealed that caspase\u20106 drives liver injury and fibrosis in metabolic dysfunction\u2010associate steatohepatitis. Here, we report that caspase\u20106 deficiency protects against high fat diet\u2010induced obesity. Both global and adipocyte\u2010specific caspase\u20106 knockout mice exhibit increased energy expenditure, reduced adiposity and inflammation, and improved glucose metabolism. Mechanistically, caspase\u20106 directly cleaves peroxisome proliferator\u2010activated receptor gamma (PPAR\u03b3) and its cofactor specificity protein 1 (SP1), thereby suppressing adipose triglyceride lipase (ATGL) expression. Caspase\u20106 deficiency restores ATGL, enhancing lipolysis and elevating fatty acyl esters of hydroxy fatty acids (FAHFAs), which alleviate inflammation and enhance insulin sensitivity. These findings uncover a novel Casp6\u2010PPAR\u03b3\/SP1\u2010ATGL axis in adipose tissue and establish caspase\u20106 as a potential therapeutic target for obesity and insulin resistance.<\/jats:p>","DOI":"10.1002\/advs.202514784","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T08:29:27Z","timestamp":1776068967000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Caspase\u20106 Controls Lipid and Energy Metabolism in Diet\u2010Induced Obesity"],"prefix":"10.1002","volume":"13","author":[{"given":"Abhishek","family":"Gupta","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Structural Biology University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjing","family":"You","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Structural Biology University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linmeng","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianfei","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meixia","family":"Pan","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianlin","family":"Han","sequence":"additional","affiliation":[{"name":"Barshop Institute for Longevity and Aging Studies University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Texas Health Science Center San Antonio  San Antonio Texas USA"},{"name":"Mays Cancer Center University of Texas Health Science Center San Antonio  San Antonio Texas USA"},{"name":"Transplant Center University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4924-0086","authenticated-orcid":false,"given":"Peng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Structural Biology University of Texas Health Science Center San Antonio  San Antonio Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008656"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010814-124414"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0542"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adg6237"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/diseases13020055"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-018-0021-8"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2391"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2017.90"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05483"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.05.002"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2337\/db08-1644"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400559"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04787-x"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.09.035"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.01.001"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI127092"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.plipres.2020.101053"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2022.109127"},{"key":"e_1_2_9_20_1","first-page":"221","article-title":"Adipose Triglyceride Lipase Regulation: An Overview","volume":"19","author":"Cerk I. 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