Bone controls browning of white adipose tissue and protects from diet-induced obesity through Schnurri-3-regulated SLIT2 secretion

Zan Li, Baohong Shi, Na Li, Jun Sun, Xiangchen Zeng, Rui Huang, Seoyeon Bok, Xiaohui Chen, Jie Han, Alisha R. Yallowitz, Shawon Debnath, Michelle Cung, Zheng Ling, Chuan-Qi Zhong, Yixang Hong, Gang Li, Mascha Koenen, Paul Cohen, Xinhui Su, Hongbin Lu (), Matthew B. Greenblatt () and Ren Xu ()
Additional contact information
Zan Li: Xiamen University
Baohong Shi: Xiamen University
Na Li: Xiamen University
Jun Sun: Weill Cornell Medicine
Xiangchen Zeng: Xiamen University
Rui Huang: Xiamen University
Seoyeon Bok: Weill Cornell Medicine
Xiaohui Chen: Xiamen University
Jie Han: Xiamen University
Alisha R. Yallowitz: Weill Cornell Medicine
Shawon Debnath: Weill Cornell Medicine
Michelle Cung: Weill Cornell Medicine
Zheng Ling: Weill Cornell Medicine
Chuan-Qi Zhong: Xiamen University
Yixang Hong: Xiamen University
Gang Li: Xiamen University
Mascha Koenen: The Rockefeller University
Paul Cohen: The Rockefeller University
Xinhui Su: Zhejiang University School of Medicine
Hongbin Lu: Central South University
Matthew B. Greenblatt: Weill Cornell Medicine
Ren Xu: Xiamen University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3−/− (Shn3−/−) mice with augmented osteoblast activity, we show Shn3−/−mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3−/−mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.

Date: 2024
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DOI: 10.1038/s41467-024-51155-6

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