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However, direct mechanisms linking OPA1 to brown adipose tissue (BAT) physiology are incompletely understood. We utilized a mouse model of selective OPA1 deletion in BAT (OPA1 BAT KO) to investigate the role of OPA1 in thermogenesis. OPA1 is required for cold-induced activation of thermogenic genes in BAT. Unexpectedly, OPA1 deficiency induced fibroblast growth factor 21 (FGF21) as a BATokine in an activating transcription factor 4 (ATF4)-dependent manner. BAT-derived FGF21 mediates an adaptive response by inducing browning of white adipose tissue, increasing resting metabolic rates, and improving thermoregulation. However, mechanisms independent of FGF21, but dependent on ATF4 induction, promote resistance to diet-induced obesity in OPA1 BAT KO mice. These findings uncover a homeostatic mechanism of BAT-mediated metabolic protection governed in part by an ATF4-FGF21 axis, which is activated independently of BAT thermogenic function.<\/jats:p>","DOI":"10.7554\/elife.66519","type":"journal-article","created":{"date-parts":[[2021,5,4]],"date-time":"2021-05-04T08:05:59Z","timestamp":1620115559000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.66519","source":"Crossref","is-referenced-by-count":81,"title":["OPA1 deletion in brown adipose tissue improves thermoregulation and systemic metabolism via FGF21"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5809-4669","authenticated-orcid":true,"given":"Renata O","family":"Pereira","sequence":"first","affiliation":[{"name":"Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. 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