Tirzepatide, a dual GLP-1 and GIP receptor agonist, promotes bone loss in obese mice via gut microbial-related metabolites

作者：Ning Chen, Mengdan Zhang, Baohong Shi, Xiumei Luo, Rui Huang, Zhengqiong Luo, Junliang He, Shengye Xue, Na Li, Zemin Ling, Hao Guo, Ren Xu, Yuejun Liu · 发表于：Journal of Orthopaedic Translation · 年份：2025 · DOI：10.1016/j.jot.2025.09.002 · 被引用次数：6 · 研究领域：Diabetes Treatment and Management、Gut microbiota and health、Bariatric Surgery and Outcomes

As a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, Tirzepatide (TZP) is a recently approved medication for treating type 2 diabetes mellitus (T2DM) and obesity; however, the effect of TZP in bone remodeling remains unclear. 1. The effect of Tirzepatide on osteoblasts and osteoclasts was observed by inducing differentiation of bone marrow mesenchymal cells (BMSCs) in vitro . 2. Db/db mice were used as a pathological model to investigate the role of TZP on bone metabolism. After TZP intervention, the feces in the intestinal tract of mice were collected for 16s rRNA gene sequencing to select the candidate gut microbiota most related to bone mass, and the effects of gut microbiota on bone metabolism were verified through subsequent microbiota supplementation experiments. 3. Metabolomics was used to analyze the difference of fecal metabolites between mice with the candidate microbiota supplement and those without, and the effect of candidate metabolites on bone metabolism was verified by the in vitro intervention of differential metabolites in BMSCs induction differentiation experiments. We found that TZP intervention resulted in a significant decrease in bone mass accrual in vivo . TZP was not indispensable to the differentiation of osteoblasts and osteoclasts in vitro . Bone and fat homeostasis were modulated by gut microbiota. We further demonstrated that the biodiversity of the gut microbiota in db/db mice w...