Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells
Abstract Non-shivering thermogenesis of brown adipose tissue (BAT) is tightly controlled by neural innervation. However, the underlying mechanism remains unclear. Here, we reveal that BAT regulates its own thermoadaptive innervation by crosstalk with Schwann cells (SCs). Loss of Olfm4 (encoding Olfa...
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60474-1 |
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| author | Mingqiang Lai Wu Zhou Wenchong Zou Lianlian Qiu Zhaoyu Liang Wanyi Chen Yiqing Wang Bin Guo Chaoran Zhao Sheng Zhang Pinglin Lai Le Hu Xiaolin Liu Yu Jiang Yinghua Chen Min-jun Huang Xiaochun Bai Zhipeng Zou |
| author_facet | Mingqiang Lai Wu Zhou Wenchong Zou Lianlian Qiu Zhaoyu Liang Wanyi Chen Yiqing Wang Bin Guo Chaoran Zhao Sheng Zhang Pinglin Lai Le Hu Xiaolin Liu Yu Jiang Yinghua Chen Min-jun Huang Xiaochun Bai Zhipeng Zou |
| author_sort | Mingqiang Lai |
| collection | DOAJ |
| description | Abstract Non-shivering thermogenesis of brown adipose tissue (BAT) is tightly controlled by neural innervation. However, the underlying mechanism remains unclear. Here, we reveal that BAT regulates its own thermoadaptive innervation by crosstalk with Schwann cells (SCs). Loss of Olfm4 (encoding Olfactomedin-4), a risk gene in human obesity, causes BAT dysfunction and reduces whole-body thermogenesis, predisposing to obesity in mice. Mechanistically, BAT-derived OLFM4 traps Noggin, an endogenous inhibitor of BMPs, liberating BMP7-BMPR1B signaling to promote SC differentiation. Conversely, Olfm4 loss reduced BMP7 signaling in mature SCs, leading to MEK/ERK-dependent dedifferentiation and dysfunction, ultimately impairing both sensory and sympathetic innervation. Thermoneutrality exposure reduces Olfm4 expression in BAT, resulting in a similar phenotype. MEK/ERK inhibition, ERK1 depletion, or cold exposure reverses this SC dedifferentiation, enhancing resistance to obesity. These findings suggest that this neurotrophic BAT-SC crosstalk controls thermoadaptive BAT innervation. Reactivating OLFM4 signaling may be a promising therapeutic strategy for obesity and related metabolic diseases. |
| format | Article |
| id | doaj-art-b64049c0d03e4e54828cd5a8df687057 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b64049c0d03e4e54828cd5a8df6870572025-08-20T02:05:41ZengNature PortfolioNature Communications2041-17232025-06-0116112010.1038/s41467-025-60474-1Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cellsMingqiang Lai0Wu Zhou1Wenchong Zou2Lianlian Qiu3Zhaoyu Liang4Wanyi Chen5Yiqing Wang6Bin Guo7Chaoran Zhao8Sheng Zhang9Pinglin Lai10Le Hu11Xiaolin Liu12Yu Jiang13Yinghua Chen14Min-jun Huang15Xiaochun Bai16Zhipeng Zou17The Fifth Affiliated Hospital, Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityKey Laboratory of Aging and Cancer Biology of Zhejiang Province, Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Hangzhou Normal UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityGuangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, The Third Affiliated Hospital of Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Pharmacology and Chemical Biology, University of Pittsburgh, School of MedicineGuangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Sciences, Southern Medical UniversityDepartment of Orthopaedics, the Third Affiliated Hospital of Southern Medical UniversityThe Fifth Affiliated Hospital, Southern Medical UniversityState Key Laboratory of Multi-organ Injury Prevention and Treatment, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical UniversityAbstract Non-shivering thermogenesis of brown adipose tissue (BAT) is tightly controlled by neural innervation. However, the underlying mechanism remains unclear. Here, we reveal that BAT regulates its own thermoadaptive innervation by crosstalk with Schwann cells (SCs). Loss of Olfm4 (encoding Olfactomedin-4), a risk gene in human obesity, causes BAT dysfunction and reduces whole-body thermogenesis, predisposing to obesity in mice. Mechanistically, BAT-derived OLFM4 traps Noggin, an endogenous inhibitor of BMPs, liberating BMP7-BMPR1B signaling to promote SC differentiation. Conversely, Olfm4 loss reduced BMP7 signaling in mature SCs, leading to MEK/ERK-dependent dedifferentiation and dysfunction, ultimately impairing both sensory and sympathetic innervation. Thermoneutrality exposure reduces Olfm4 expression in BAT, resulting in a similar phenotype. MEK/ERK inhibition, ERK1 depletion, or cold exposure reverses this SC dedifferentiation, enhancing resistance to obesity. These findings suggest that this neurotrophic BAT-SC crosstalk controls thermoadaptive BAT innervation. Reactivating OLFM4 signaling may be a promising therapeutic strategy for obesity and related metabolic diseases.https://doi.org/10.1038/s41467-025-60474-1 |
| spellingShingle | Mingqiang Lai Wu Zhou Wenchong Zou Lianlian Qiu Zhaoyu Liang Wanyi Chen Yiqing Wang Bin Guo Chaoran Zhao Sheng Zhang Pinglin Lai Le Hu Xiaolin Liu Yu Jiang Yinghua Chen Min-jun Huang Xiaochun Bai Zhipeng Zou Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells Nature Communications |
| title | Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells |
| title_full | Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells |
| title_fullStr | Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells |
| title_full_unstemmed | Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells |
| title_short | Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells |
| title_sort | brown adipose tissue secretes olfm4 to coordinate sensory and sympathetic innervation via schwann cells |
| url | https://doi.org/10.1038/s41467-025-60474-1 |
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