Nature communications · 2026
Adipocytic sclerostin loop3-LRP4 interaction required by sclerostin to impair whole-body lipid and glucose metabolism.
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Jiang Hewen, Tao Xiaohui, Yu Sifan, Zhang Yihao, Ma Yuan, Li Nanxi, Wang Shenghang, Zhang Ning, Yang Xin, Ding Shijian, Zhong Chuanxin, Li Haitian, Li Zhanghao, Wen Xiaoxin, Zhang Huarui, Chen Zefeng, Sun Meiheng, Luo Hang, Ren Meishen, Lei Chongguang, Yu Yuanyuan, Liu Jin, Zhang Zongkang, Lyu Aiping, Sheng Hui, Li Dijie, Wang Luyao, Zhang Ge, Zhang Bao-Ting
Аннотация
Sclerostin, which has three loops, inhibits bone formation and impairs whole-body lipid and glucose metabolism. The marketed therapeutic sclerostin antibody for postmenopausal osteoporosis (POP) mainly targeting loop2 promotes bone formation and improves whole-body lipid and glucose metabolism. However, FDA/EMA warns of its cardiovascular risk. We previously demonstrate that sclerostin loop3 contributes to the inhibitory effect of sclerostin on bone formation but not its cardioprotective effect. Here we find elevated serum sclerostin levels in both POP-T2DM patients and newly-diagnosed T2DM patients and further demonstrate that sclerostin loop3 participates in the impairment effect of sclerostin on whole-body lipid and glucose metabolism in vivo. Mechanistically, specific blockade of adipocytic sclerostin loop3-LRP4 interaction attenuates the impairment effect of sclerostin on lipid and glucose metabolism in vitro and in vivo. This study provides an innovative strategy, blocking adipocytic sclerostin loop3-LRP4 interaction, to normalize lipid and glucose metabolism in POP-T2DM patients, in cardiovascular safety.