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Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP\/TAZ signalling in adipocytes by deletion of the upstream regulators <jats:italic>Lats1<\/jats:italic> and <jats:italic>Lats2<\/jats:italic> results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP\/TAZ\u2013TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP\/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo\u2013YAP\/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.<\/jats:p>","DOI":"10.1038\/s42255-024-01045-4","type":"journal-article","created":{"date-parts":[[2024,5,29]],"date-time":"2024-05-29T16:02:05Z","timestamp":1716998525000},"page":"847-860","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Hippo\u2013YAP\/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7802-2187","authenticated-orcid":false,"given":"Sungwoo","family":"Choi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3397-232X","authenticated-orcid":false,"given":"Ju-Gyeong","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1414-2328","authenticated-orcid":false,"given":"Yen T. 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