A nuclear ERK-ATF5 axis coordinates mitochondrial metabolism and thermogenic gene expression in brown adipocytes.
9 affiliations
- 1Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine , Daejeon, Republic of Korea.
- 2Department of Medical Science, Chungnam National University School of Medicine , Daejeon, Republic of Korea.
- 3Department of Life Sciences, Gwangju Institute of Science and Technology , Gwangju, Republic of Korea.
- 4Integrated Institute of Biomedical Research, Gwangju Institute of Science and Technology , Gwangju, Republic of Korea.
- 5Department of Orthopaedic Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University , Guangzhou, Guangdong, P.R. China.
- 6Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University , Seoul, Republic of Korea.
- 7Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB) , Daejeon, Republic of Korea.
- 8Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology , Daejeon, Republic of Korea.
- 9Department of Internal Medicine, Chungnam National University School of Medicine , Daejeon, Republic of Korea.
Abstract
Graphical abstract
Abstract
Obesity and diabetes arise from disrupted energy homeostasis, underscoring the need to identify mechanisms that enhance energy expenditure. Brown adipose tissue dissipates energy through mitochondria-dependent non-shivering thermogenesis; however, the transcriptional regulators coordinating this process remain incompletely defined. Here, we investigated the role of activating transcription factor 5 in thermogenic programming and mitochondrial metabolism in brown adipocytes using in vivo and in vitro models. Cold exposure and β3-adrenergic stimulation induced activating transcription factor 5 expression in brown adipose tissue and differentiated adipocytes, accompanied by activation of thermogenic gene programs. Mechanistically, activating transcription factor 5 functioned downstream of a nuclear protein kinase A-extracellular signal-regulated kinase pathway, whose nuclear activation was required for its induction and for upregulation of uncoupling protein 1. Loss of activating transcription factor 5 impaired thermogenic gene expression, reduced mitochondrial stress response and lipolytic programs, diminished mitochondrial oxidative capacity, and suppressed fatty acid oxidation, including reduced incorporation of fatty acid-derived carbons into the tricarboxylic acid cycle. Transcriptomic analysis revealed coordinated repression of pathways related to fatty acid oxidation, oxidative phosphorylation, and thermogenesis in activating transcription factor 5-deficient adipocytes. Live-cell imaging further confirmed that β3-adrenergic stimulation selectively enhanced nuclear kinase activity, establishing a nuclear-localized signaling axis. Together, these findings identify activating transcription factor 5 as a key transcriptional regulator linking mitochondrial metabolism and thermogenic gene expression, supporting its potential as a therapeutic target for enhancing energy expenditure in metabolic disease.
Related
- Pharmacological melatonin induces mitochondrial dysfunction and alters extracellular nucleotide metabolism and CD39/CD73 expression in human melanoma cells.
- Acute loss of PLIN5 in brown adipocytes reveals its indispensable role in maintaining mitochondrial function and cold tolerance
- ACAT1/SOAT1 governs mitochondrial dynamics and thermogenesis via the mTOR-MFN2-USP2 axis in brown adipocytes
- Empagliflozin attenuates ISO-induced myocardial injury through PGC-1α-mediated mitochondrial biogenesis and improved fatty acid metabolism
- Early mitophagy defects and impaired mitochondrial energy metabolism drive target organ damage progression: Lessons from the Fabry heart
BibTeX
@article{jang2026nuclear,
title = {{A nuclear ERK-ATF5 axis coordinates mitochondrial metabolism and thermogenic gene expression in brown adipocytes.}},
author = {Hyo Ju Jang and Yeongjun Suh and Jingwen Tian and Ho Yeop Lee and Ji Sun Moon and Ha Thi Nga and Thi Linh Nguyen and Alfin Mohammad Abdillah and Gyu Min Lim and Dong Wook Choi and Chuna Kim and Yonghoon Kwon and Hyon-Seung Yi},
journal = {The Journal of endocrinology},
year = {2026},
month = oct,
doi = {10.1530/joe-26-0101},
url = {https://europepmc.org/article/MED/42847123},
note = {CC BY},
}
RIS
TY - JOUR
TI - A nuclear ERK-ATF5 axis coordinates mitochondrial metabolism and thermogenic gene expression in brown adipocytes.
AU - Hyo Ju Jang
AU - Yeongjun Suh
AU - Jingwen Tian
AU - Ho Yeop Lee
AU - Ji Sun Moon
AU - Ha Thi Nga
AU - Thi Linh Nguyen
AU - Alfin Mohammad Abdillah
AU - Gyu Min Lim
AU - Dong Wook Choi
AU - Chuna Kim
AU - Yonghoon Kwon
AU - Hyon-Seung Yi
PY - 2026
DA - 2026/10/01
JO - The Journal of endocrinology
DO - 10.1530/joe-26-0101
UR - https://europepmc.org/article/MED/42847123
AB - Graphical abstract Abstract Obesity and diabetes arise from disrupted energy homeostasis, underscoring the need to identify mechanisms that enhance energy expenditure. Brown adipose tissue dissipates energy through mitochondria-dependent non-shivering thermogenesis; however, the transcriptional regulators coordinating this process remain incompletely defined. Here, we investigated the role of activating transcription factor 5 in thermogenic programming and mitochondrial metabolism in brown adipocytes using in vivo and in vitro models. Cold exposure and β3-adrenergic stimulation induced activating transcription factor 5 expression in brown adipose tissue and differentiated adipocytes, accompanied by activation of thermogenic gene programs. Mechanistically, activating transcription factor 5 functioned downstream of a nuclear protein kinase A-extracellular signal-regulated kinase pathway, whose nuclear activation was required for its induction and for upregulation of uncoupling protein 1. Loss of activating transcription factor 5 impaired thermogenic gene expression, reduced mitochondrial stress response and lipolytic programs, diminished mitochondrial oxidative capacity, and suppressed fatty acid oxidation, including reduced incorporation of fatty acid-derived carbons into the tricarboxylic acid cycle. Transcriptomic analysis revealed coordinated repression of pathways related to fatty acid oxidation, oxidative phosphorylation, and thermogenesis in activating transcription factor 5-deficient adipocytes. Live-cell imaging further confirmed that β3-adrenergic stimulation selectively enhanced nuclear kinase activity, establishing a nuclear-localized signaling axis. Together, these findings identify activating transcription factor 5 as a key transcriptional regulator linking mitochondrial metabolism and thermogenic gene expression, supporting its potential as a therapeutic target for enhancing energy expenditure in metabolic disease.
SN - 0022-0795
SN - 1479-6805
ER -