Journal article
Increased Brown Adipose Tissue Thermogenesis in Phenylketonuria
MedComm (2020), Vol.7(6), e70820
06/01/2026
DOI: 10.1002/mco2.70820
PMCID: PMC13263790
PMID: 42292855
Abstract
ABSTRACT Phenylketonuria (PKU), the most common autosomal‑recessive disorder of amino acid metabolism, is characterized by neurological impairment and systemic metabolic alterations caused by chronically elevated phenylalanine (Phe) levels. 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‑activated protein kinase (AMPK) activity and increased sympathetic drive to BAT. Consistently, analysis of public single‑cell RNA‑sequencing 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‐induced FGF21 disrupts energy homeostasis via hypothalamic AMPK inhibition.
Details
- Title: Subtitle
- Increased Brown Adipose Tissue Thermogenesis in Phenylketonuria
- Creators
- Noemí López-ReyAlba Cabaleiro - Universidade de Santiago de CompostelaMaría P Pata - Biostatistical Consulting (United States)Marion Peyrou - Hospital Sant Joan de Déu BarcelonaÁnxela Estévez-Salguero - Universidade de Santiago de CompostelaPaola Fernández-SanmartínDonald A Morgan - University of IowaVitor Ferreira - Universidade de Santiago de CompostelaPaula Sánchez-Pintos - Instituto de Investigación Sanitaria de SantiagoCintia Folgueira - Universidade de Santiago de CompostelaCarlos Diéguez - Universidade de Santiago de CompostelaAdela Urisarri - Instituto de Investigación Sanitaria de SantiagoIsmael González-García - Universidade de Santiago de CompostelaLuisa M Seoane - Instituto de Salud Carlos IIIKamal Rahmouni - University of IowaFrancesc Villarroya - Hospital Sant Joan de Déu BarcelonaMaría L Couce - Centro de Investigación en Red en Enfermedades CardiovascularesRubén Nogueiras - Universidade de Santiago de CompostelaMiguel López - Universidade de Santiago de Compostela
- Resource Type
- Journal article
- Publication Details
- MedComm (2020), Vol.7(6), e70820
- DOI
- 10.1002/mco2.70820
- PMID
- 42292855
- PMCID
- PMC13263790
- NLM abbreviation
- MedComm (2020)
- ISSN
- 2688-2663
- eISSN
- 2688-2663
- Publisher
- John Wiley & Sons, Inc
- Grant note
- US National Institutes of Health: R01 HL162773, R01 HL172944 European Research Council: 2019-WATCH-810331 Ministerio de Ciencia e Innovacin FEDER Program of EU: PID2023-146781OB-I00, PID2021-126096NB-I00, PID2024-162486OB-I00, CPP2024-011411, PDC2025-166594-I00 US Department of Veterans Affairs: I01 BX004249, IK6 BX006040
The research leading to these results has received funding from the Ministerio de Ciencia e Innovacion, co-funded by the FEDER Program of EU (FV: PID2023-146781OB-I00; RN: PID2021-126096NB-I00; ML: PID2024-162486OB-I00, CPP2024-011411, and PDC2025-166594-I00); the European Research Council (RN: ERC Synergy Grant-2019-WATCH-810331); the US National Institutes of Health (KR: R01 HL162773 and R01 HL172944); and the US Department of Veterans Affairs (KR: I01 BX004249 and IK6 BX006040). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
- Language
- English
- Date published
- 06/01/2026
- Academic Unit
- Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9985172994402771
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