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PKU patients have long been reported to display reduced metabolic rate and impaired thermoregulation, yet the role of brown adipose tissue (BAT) in this condition remains unknown. Here, noninvasive infrared thermography was used to assess BAT activity in a cohort primarily comprising children and adolescents including controls, mild hyperphenylalaninemia (MHPA), and PKU patients, while circulating metabolic and hormonal parameters were analyzed for associations with BAT temperature. Despite overall normothermia, individuals with PKU exhibited higher BAT temperature than both control and MHPA patients, which correlated with circulating fibroblast growth factor 21 (FGF21) and thyroid hormones. To gain mechanistic insight, rats and mice were centrally treated with FGF21, reproducing the BAT thermogenic phenotype along with decreased hypothalamic AMP\u2011activated protein kinase (AMPK) activity and increased sympathetic drive to BAT. Consistently, analysis of public single\u2011cell RNA\u2011sequencing data revealed convergent expression of AMPK, thyroid hormone receptor, and FGF21 receptor signaling in specific hypothalamic neuronal populations. These findings reveal enhanced BAT thermogenesis in PKU and demonstrate that Phe\u2010induced FGF21 disrupts energy homeostasis via hypothalamic AMPK inhibition.<\/jats:p>","DOI":"10.1002\/mco2.70820","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T10:18:13Z","timestamp":1781345893000},"source":"Crossref","is-referenced-by-count":1,"title":["Increased Brown Adipose Tissue Thermogenesis in Phenylketonuria"],"prefix":"10.1002","volume":"7","author":[{"given":"Noem\u00ed","family":"L\u00f3pez\u2010Rey","sequence":"first","affiliation":[{"name":"Department of Physiology, CIMUS University of Santiago de Compostela  Santiago de Compostela Spain"},{"name":"Department of Pediatrics, Neonatology Service, University Clinical Hospital of Santiago de Compostela Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela (IDIS) and Spanish Network in Maternal Neonatal, Child and Developmental Health Research (RICORS\u2011SAMID)  Santiago de Compostela Spain"},{"name":"Research Unit Hospital Lucus Augusti  Lugo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Cabaleiro","sequence":"additional","affiliation":[{"name":"Department of Physiology, CIMUS University of Santiago de Compostela  Santiago de Compostela Spain"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN)  Santiago de Compostela Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda P.","family":"Pata","sequence":"additional","affiliation":[{"name":"Biostatech Advice Training and Innovation in Biostatistics S.L.  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