Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells

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 () and Zhipeng Zou ()
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Mingqiang Lai: Southern Medical University
Wu Zhou: Southern Medical University
Wenchong Zou: Hangzhou Normal University
Lianlian Qiu: Southern Medical University
Zhaoyu Liang: Southern Medical University
Wanyi Chen: Southern Medical University
Yiqing Wang: Southern Medical University
Bin Guo: Southern Medical University
Chaoran Zhao: Southern Medical University
Sheng Zhang: Southern Medical University
Pinglin Lai: The Third Affiliated Hospital of Southern Medical University
Le Hu: Southern Medical University
Xiaolin Liu: Southern Medical University
Yu Jiang: School of Medicine
Yinghua Chen: Southern Medical University
Min-jun Huang: the Third Affiliated Hospital of Southern Medical University
Xiaochun Bai: Southern Medical University
Zhipeng Zou: Southern Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60474-1

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