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Peer-reviewedCC BY 4.0Experimental and Molecular Medicine

DUSP4 activates adipocyte thermogenesis via CRTC3 dephosphorylation-dependent UCP1 expression

  • Min Jeong Son1
  • Hae Un Kook1
  • Jaeeun Jung1,2
  • Se-Jun Park3
  • Young Joo Jeon1
  • Kyoung-Jin Oh1,2
  • Eun-Woo Lee1,2,4
  • Baek Soo Han2,5
  • Jang Hyun Choi6
  • Kwang-Hee Bae1
  • Won Kon Kim1,2
6 affiliations
  1. 1Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
  2. 2Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, Republic of Korea
  3. 3Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 145, Anam-ro, Seongbuk-gu, Seoul, Republic of Korea
  4. 4School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
  5. 5Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea
  6. 6Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea
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Abstract

Obesity arises when a chronic energy surplus overwhelms the storage capacity of adipocytes and subsequently causes systemic metabolic dysfunction. Adaptive thermogenesis, primarily mediated by uncoupling protein 1 (Ucp1) in adipocytes, serves to counteract obesity by dissipating excess energy as heat. Despite extensive studies on thermogenic regulation, the phosphatases that regulate this protective metabolic pathway remain poorly understood. Here we identify dual-specificity phosphatase 4 (Dusp4) as a critical modulator of adipocyte thermogenesis via direct modulation of CREB-regulated transcription coactivator 3 (Crtc3). Dusp4-knockout mice exhibit impaired thermogenic capacity, diminished Ucp1 expression, and increased susceptibility to diet-induced obesity coupled with severe insulin resistance. Mechanistically, Dusp4 directly dephosphorylates serine residues on Crtc3, facilitating its nuclear translocation and subsequent transcriptional activation of Ucp1. Depot-targeted restoration of catalytically active Dusp4 in inguinal adipose tissue rescues local thermogenic gene expression and reinstates Crtc3 dephosphorylation-dependent Ucp1 induction in Dusp4-knockout mice. Collectively, these findings identify Dusp4 as a key upstream phosphatase orchestrating the Crtc3–Ucp1 thermogenic axis, and highlight its potential as a therapeutic target for obesity-associated metabolic disorders.

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Cite

BibTeXRIS
BibTeX
@article{son2026dusp4,
  title = {{DUSP4 activates adipocyte thermogenesis via CRTC3 dephosphorylation-dependent UCP1 expression}},
  author = {Min Jeong Son and Hae Un Kook and Jaeeun Jung and Se-Jun Park and Young Joo Jeon and Kyoung-Jin Oh and Eun-Woo Lee and Baek Soo Han and Jang Hyun Choi and Kwang-Hee Bae and Won Kon Kim},
  journal = {Experimental and Molecular Medicine},
  year = {2026},
  month = oct,
  doi = {10.1038/s12276-026-01850-9},
  url = {https://doi.org/10.1038/s12276-026-01850-9},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - DUSP4 activates adipocyte thermogenesis via CRTC3 dephosphorylation-dependent UCP1 expression
AU  - Min Jeong Son
AU  - Hae Un Kook
AU  - Jaeeun Jung
AU  - Se-Jun Park
AU  - Young Joo Jeon
AU  - Kyoung-Jin Oh
AU  - Eun-Woo Lee
AU  - Baek Soo Han
AU  - Jang Hyun Choi
AU  - Kwang-Hee Bae
AU  - Won Kon Kim
PY  - 2026
DA  - 2026/10/01
JO  - Experimental and Molecular Medicine
DO  - 10.1038/s12276-026-01850-9
UR  - https://doi.org/10.1038/s12276-026-01850-9
AB  - Obesity arises when a chronic energy surplus overwhelms the storage capacity of adipocytes and subsequently causes systemic metabolic dysfunction. Adaptive thermogenesis, primarily mediated by uncoupling protein 1 (Ucp1) in adipocytes, serves to counteract obesity by dissipating excess energy as heat. Despite extensive studies on thermogenic regulation, the phosphatases that regulate this protective metabolic pathway remain poorly understood. Here we identify dual-specificity phosphatase 4 (Dusp4) as a critical modulator of adipocyte thermogenesis via direct modulation of CREB-regulated transcription coactivator 3 (Crtc3). Dusp4-knockout mice exhibit impaired thermogenic capacity, diminished Ucp1 expression, and increased susceptibility to diet-induced obesity coupled with severe insulin resistance. Mechanistically, Dusp4 directly dephosphorylates serine residues on Crtc3, facilitating its nuclear translocation and subsequent transcriptional activation of Ucp1. Depot-targeted restoration of catalytically active Dusp4 in inguinal adipose tissue rescues local thermogenic gene expression and reinstates Crtc3 dephosphorylation-dependent Ucp1 induction in Dusp4-knockout mice. Collectively, these findings identify Dusp4 as a key upstream phosphatase orchestrating the Crtc3–Ucp1 thermogenic axis, and highlight its potential as a therapeutic target for obesity-associated metabolic disorders.
SN  - 2092-6413
SN  - 1226-3613
ER  -