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Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.<\/jats:p>","DOI":"10.2337\/db21-1172","type":"journal-article","created":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T13:01:40Z","timestamp":1655384500000},"page":"59-70","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":44,"title":["Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy"],"prefix":"10.2337","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7764-6529","authenticated-orcid":false,"given":"Caleigh","family":"Mandel-Brehm","sequence":"first","affiliation":[{"name":"1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara 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