Gut Microbiota Modulates Obesity‐Associated Skeletal Deterioration Through Macrophage Aging and Grancalcin Secretion
Abstract Obesity is associated with skeletal deterioration and increased fracture risk, but the underlying mechanism is unclear. Herein, it is shown that obese gut microbiota promotes skeletal deterioration by inducing bone marrow macrophages (BMMs) senescence and grancalcin (GCA) secretion. Obese m...
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Wiley
2025-07-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202502634 |
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| author | Min Huang Mei Huang Ling Liu Fang Yang Chen He Yu‐Chen Sun Yu‐Rui Jiao Xiang Tang Jing Hou Kai‐Xuan Chen Wen‐Zhen He Jie Wei Hui‐Ling Chen Xia Li Chao Zeng Guang‐Hua Lei Chang‐Jun Li |
| author_facet | Min Huang Mei Huang Ling Liu Fang Yang Chen He Yu‐Chen Sun Yu‐Rui Jiao Xiang Tang Jing Hou Kai‐Xuan Chen Wen‐Zhen He Jie Wei Hui‐Ling Chen Xia Li Chao Zeng Guang‐Hua Lei Chang‐Jun Li |
| author_sort | Min Huang |
| collection | DOAJ |
| description | Abstract Obesity is associated with skeletal deterioration and increased fracture risk, but the underlying mechanism is unclear. Herein, it is shown that obese gut microbiota promotes skeletal deterioration by inducing bone marrow macrophages (BMMs) senescence and grancalcin (GCA) secretion. Obese mice and those receiving obese fecal microbiota transplants exhibit increased senescent macrophages and elevated GCA expression in the bone marrow. In a study of 40 participants, it is found that obese patients are associated with higher serum GCA levels. It is further revealed that obese gut‐microbiota derived lipopolysaccharides (LPS) stimulate GCA expression in senescent BMMs via activating Toll‐like receptor 4 pathway. Mice with depletion of the Gca gene are resistant to the negative effects of obesity and LPS on bone. Moreover, neutralizing antibody against GCA mitigates skeletal deterioration in obese mice and LPS‐induced chronic inflammation mouse model. The data suggest that the interaction between gut microbiota and the immune system contributes to obesity‐associated skeletal deterioration, and targeting senescent macrophages and GCA shows potential of protecting skeletal health in obese population. |
| format | Article |
| id | doaj-art-e0eba02be7bd4e95b766d56c4c0ca658 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-e0eba02be7bd4e95b766d56c4c0ca6582025-08-20T03:15:29ZengWileyAdvanced Science2198-38442025-07-011228n/an/a10.1002/advs.202502634Gut Microbiota Modulates Obesity‐Associated Skeletal Deterioration Through Macrophage Aging and Grancalcin SecretionMin Huang0Mei Huang1Ling Liu2Fang Yang3Chen He4Yu‐Chen Sun5Yu‐Rui Jiao6Xiang Tang7Jing Hou8Kai‐Xuan Chen9Wen‐Zhen He10Jie Wei11Hui‐Ling Chen12Xia Li13Chao Zeng14Guang‐Hua Lei15Chang‐Jun Li16Department of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Clinical Laboratory Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaHunan Key Laboratory of Joint Degeneration and Injury Changsha 410008 ChinaDepartment of Endocrine Subspecialty of Gerontology Xiangya Hospital, Central South University Changsha 410008 ChinaDepartment of General Medicine The Fifth Affiliated Hospital of Xinjiang Medical University Urumqi 830000 ChinaHunan Key Laboratory of Joint Degeneration and Injury Changsha 410008 ChinaHunan Key Laboratory of Joint Degeneration and Injury Changsha 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital Central South University Changsha 410008 ChinaAbstract Obesity is associated with skeletal deterioration and increased fracture risk, but the underlying mechanism is unclear. Herein, it is shown that obese gut microbiota promotes skeletal deterioration by inducing bone marrow macrophages (BMMs) senescence and grancalcin (GCA) secretion. Obese mice and those receiving obese fecal microbiota transplants exhibit increased senescent macrophages and elevated GCA expression in the bone marrow. In a study of 40 participants, it is found that obese patients are associated with higher serum GCA levels. It is further revealed that obese gut‐microbiota derived lipopolysaccharides (LPS) stimulate GCA expression in senescent BMMs via activating Toll‐like receptor 4 pathway. Mice with depletion of the Gca gene are resistant to the negative effects of obesity and LPS on bone. Moreover, neutralizing antibody against GCA mitigates skeletal deterioration in obese mice and LPS‐induced chronic inflammation mouse model. The data suggest that the interaction between gut microbiota and the immune system contributes to obesity‐associated skeletal deterioration, and targeting senescent macrophages and GCA shows potential of protecting skeletal health in obese population.https://doi.org/10.1002/advs.202502634obesityskeletal deteriorationimmunosenescencegrancalcingut‐microbiota |
| spellingShingle | Min Huang Mei Huang Ling Liu Fang Yang Chen He Yu‐Chen Sun Yu‐Rui Jiao Xiang Tang Jing Hou Kai‐Xuan Chen Wen‐Zhen He Jie Wei Hui‐Ling Chen Xia Li Chao Zeng Guang‐Hua Lei Chang‐Jun Li Gut Microbiota Modulates Obesity‐Associated Skeletal Deterioration Through Macrophage Aging and Grancalcin Secretion Advanced Science obesity skeletal deterioration immunosenescence grancalcin gut‐microbiota |
| title | Gut Microbiota Modulates Obesity‐Associated Skeletal Deterioration Through Macrophage Aging and Grancalcin Secretion |
| title_full | Gut Microbiota Modulates Obesity‐Associated Skeletal Deterioration Through Macrophage Aging and Grancalcin Secretion |
| title_fullStr | Gut Microbiota Modulates Obesity‐Associated Skeletal Deterioration Through Macrophage Aging and Grancalcin Secretion |
| title_full_unstemmed | Gut Microbiota Modulates Obesity‐Associated Skeletal Deterioration Through Macrophage Aging and Grancalcin Secretion |
| title_short | Gut Microbiota Modulates Obesity‐Associated Skeletal Deterioration Through Macrophage Aging and Grancalcin Secretion |
| title_sort | gut microbiota modulates obesity associated skeletal deterioration through macrophage aging and grancalcin secretion |
| topic | obesity skeletal deterioration immunosenescence grancalcin gut‐microbiota |
| url | https://doi.org/10.1002/advs.202502634 |
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