Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity

Chuanxin Zhong; Nanxi Li; Shengzheng Wang; Dijie Li; Zhihua Yang; Lin Du; Guangxin Huang; Haitian Li; Wing Sze Yeung; Shan He; Shuting Ma; Zhuqian Wang; Hewen Jiang; Huarui Zhang; Zhanghao Li; Xiaoxin Wen; Song Xue; Xiaohui Tao; Haorui Li; Duoli Xie; Yihao Zhang; Zefeng Chen; Junqin Wang; Jianfeng Yan; Zhengming Liang; Zongkang Zhang; Zhigang Zhong; Zeting Wu; Chao Wan; Chao Liang; Luyao Wang; Sifan Yu; Yuan Ma; Yuanyuan Yu; Fangfei Li; Yang Chen; Baoting Zhang; Aiping Lyu; Fuzeng Ren; Hong Zhou; Jin Liu; Ge Zhang

doi:10.1038/s41467-024-52965-4

Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity

Chuanxin Zhong, Nanxi Li, Shengzheng Wang, Dijie Li, Zhihua Yang, Lin Du, Guangxin Huang, Haitian Li, Wing Sze Yeung, Shan He, Shuting Ma, Zhuqian Wang, Hewen Jiang, Huarui Zhang, Zhanghao Li, Xiaoxin Wen, Song Xue, Xiaohui Tao, Haorui Li, Duoli XieYihao Zhang, Zefeng Chen, Junqin Wang, Jianfeng Yan, Zhengming Liang, Zongkang Zhang, Zhigang Zhong, Zeting Wu, Chao Wan, Chao Liang, Luyao Wang, Sifan Yu, Yuan Ma, Yuanyuan Yu, Fangfei Li, Yang Chen, Baoting Zhang, Aiping Lyu^*, Fuzeng Ren^*, Hong Zhou^*, Jin Liu^*, Ge Zhang^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

Abstract

Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

Original language	English
Article number	8588
Number of pages	18
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-52965-4
Publication status	Published - 4 Oct 2024

Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Zhong, C., Li, N., Wang, S., Li, D., Yang, Z., Du, L., Huang, G., Li, H., Yeung, W. S., He, S., Ma, S., Wang, Z., Jiang, H., Zhang, H., Li, Z., Wen, X., Xue, S., Tao, X., Li, H., ... Zhang, G. (2024). Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity. Nature Communications, 15(1), Article 8588. https://doi.org/10.1038/s41467-024-52965-4

@article{92a2880f7bc14d6b8a784a7f88a3ff55,

title = "Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity",

abstract = "Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.",

author = "Chuanxin Zhong and Nanxi Li and Shengzheng Wang and Dijie Li and Zhihua Yang and Lin Du and Guangxin Huang and Haitian Li and Yeung, {Wing Sze} and Shan He and Shuting Ma and Zhuqian Wang and Hewen Jiang and Huarui Zhang and Zhanghao Li and Xiaoxin Wen and Song Xue and Xiaohui Tao and Haorui Li and Duoli Xie and Yihao Zhang and Zefeng Chen and Junqin Wang and Jianfeng Yan and Zhengming Liang and Zongkang Zhang and Zhigang Zhong and Zeting Wu and Chao Wan and Chao Liang and Luyao Wang and Sifan Yu and Yuan Ma and Yuanyuan Yu and Fangfei Li and Yang Chen and Baoting Zhang and Aiping Lyu and Fuzeng Ren and Hong Zhou and Jin Liu and Ge Zhang",

note = "This work was supported by Theme-based Research Scheme (T12-201/20-R, A.P.L.) and General Research Fund (12106924 J.L., 12136616 J.L., 12103519 J.L., 12102120 Y.Y.Y., 12102322 Y.Y.Y., 12100921 G.Z., and 12102223 G.Z.) and Early Career Scheme (22102823 J.L.) of Research Grants Council of Hong Kong SAR. This work is also supported by 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab, No: 2020B1212030006 A.P.L.), Interdisciplinary Research Clusters Matching Scheme of Hong Kong Baptist University (RC-IRCs/17-18/02 G.Z.), Research Matching Grant Scheme of Hong Kong Baptist University (RMGS2023 _15_03 G.Z.), Inter-institutional Collaborative Research Scheme from Hong Kong Baptist University (Project No. RC-ICRS/19-20/01 G.Z.), International Science and Technology Corporation Key Program of Jiangxi Province (20232BBH80012 A.P.L.& J.L.), The National Key R&D Program of China (2018YFA0800804 G.Z.), Youth{\textquoteright}s Project of Guangdong Basic and Applied Basic Research Fund (2022A1515110044 D.J.L.). This work is also supported by The Young Scientists Fund of the National Natural Science Foundation of China (82304378 S.F.Y.), Guangdong-Hong Kong Technology Cooperation Funding Scheme (GHP/149/21GD, 2023A0505010015 G.Z.), The National Natural Science Foundation of China (52371251 F.Z.R.), The Fundamental and Applied Fundamental Research Fund of Guangdong Province (2022B1515120082 F.Z.R.), and The National Natural Science Foundation of China (82373733 S.Z.W.). Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = oct,

day = "4",

doi = "10.1038/s41467-024-52965-4",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Zhong, C, Li, N, Wang, S, Li, D, Yang, Z, Du, L, Huang, G, Li, H, Yeung, WS, He, S, Ma, S, Wang, Z, Jiang, H, Zhang, H, Li, Z, Wen, X, Xue, S, Tao, X, Li, H, Xie, D, Zhang, Y, Chen, Z, Wang, J, Yan, J, Liang, Z, Zhang, Z, Zhong, Z, Wu, Z, Wan, C, Liang, C, Wang, L, Yu, S, Ma, Y , Yu, Y , Li, F, Chen, Y, Zhang, B, Lyu, A, Ren, F, Zhou, H, Liu, J & Zhang, G 2024, 'Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity', Nature Communications, vol. 15, no. 1, 8588. https://doi.org/10.1038/s41467-024-52965-4

TY - JOUR

T1 - Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity

AU - Zhong, Chuanxin

AU - Li, Nanxi

AU - Wang, Shengzheng

AU - Li, Dijie

AU - Yang, Zhihua

AU - Du, Lin

AU - Huang, Guangxin

AU - Li, Haitian

AU - Yeung, Wing Sze

AU - He, Shan

AU - Ma, Shuting

AU - Wang, Zhuqian

AU - Jiang, Hewen

AU - Zhang, Huarui

AU - Li, Zhanghao

AU - Wen, Xiaoxin

AU - Xue, Song

AU - Tao, Xiaohui

AU - Li, Haorui

AU - Xie, Duoli

AU - Zhang, Yihao

AU - Chen, Zefeng

AU - Wang, Junqin

AU - Yan, Jianfeng

AU - Liang, Zhengming

AU - Zhang, Zongkang

AU - Zhong, Zhigang

AU - Wu, Zeting

AU - Wan, Chao

AU - Liang, Chao

AU - Wang, Luyao

AU - Yu, Sifan

AU - Ma, Yuan

AU - Yu, Yuanyuan

AU - Li, Fangfei

AU - Chen, Yang

AU - Zhang, Baoting

AU - Lyu, Aiping

AU - Ren, Fuzeng

AU - Zhou, Hong

AU - Liu, Jin

AU - Zhang, Ge

N1 - This work was supported by Theme-based Research Scheme (T12-201/20-R, A.P.L.) and General Research Fund (12106924 J.L., 12136616 J.L., 12103519 J.L., 12102120 Y.Y.Y., 12102322 Y.Y.Y., 12100921 G.Z., and 12102223 G.Z.) and Early Career Scheme (22102823 J.L.) of Research Grants Council of Hong Kong SAR. This work is also supported by 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong-Hong Kong-Macau Joint Lab, No: 2020B1212030006 A.P.L.), Interdisciplinary Research Clusters Matching Scheme of Hong Kong Baptist University (RC-IRCs/17-18/02 G.Z.), Research Matching Grant Scheme of Hong Kong Baptist University (RMGS2023 _15_03 G.Z.), Inter-institutional Collaborative Research Scheme from Hong Kong Baptist University (Project No. RC-ICRS/19-20/01 G.Z.), International Science and Technology Corporation Key Program of Jiangxi Province (20232BBH80012 A.P.L.& J.L.), The National Key R&D Program of China (2018YFA0800804 G.Z.), Youth’s Project of Guangdong Basic and Applied Basic Research Fund (2022A1515110044 D.J.L.). This work is also supported by The Young Scientists Fund of the National Natural Science Foundation of China (82304378 S.F.Y.), Guangdong-Hong Kong Technology Cooperation Funding Scheme (GHP/149/21GD, 2023A0505010015 G.Z.), The National Natural Science Foundation of China (52371251 F.Z.R.), The Fundamental and Applied Fundamental Research Fund of Guangdong Province (2022B1515120082 F.Z.R.), and The National Natural Science Foundation of China (82373733 S.Z.W.). Publisher Copyright: © The Author(s) 2024.

PY - 2024/10/4

Y1 - 2024/10/4

N2 - Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

AB - Excessive glucocorticoid (GC) action is linked to various metabolic disorders. Recent findings suggest that disrupting skeletal GC signaling prevents bone loss and alleviates metabolic disorders in high-fat diet (HFD)-fed obese mice, underpinning the neglected contribution of skeletal GC action to obesity and related bone loss. Here, we show that the elevated expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme driving local GC activation, and GC signaling in osteoblasts, are associated with bone loss and obesity in HFD-fed male mice. Osteoblast-specific 11β-HSD1 knockout male mice exhibit resistance to HFD-induced bone loss and metabolic disorders. Mechanistically, elevated 11β-HSD1 restrains glucose uptake and osteogenic activity in osteoblast. Pharmacologically inhibiting osteoblastic 11β-HSD1 by using bone-targeted 11β-HSD1 inhibitor markedly promotes bone formation, ameliorates glucose handling and mitigated obesity in HFD-fed male mice. Taken together, our study demonstrates that osteoblastic 11β-HSD1 directly contributes to HFD-induced bone loss, glucose handling impairment and obesity.

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UR - https://www.nature.com/articles/s41467-024-52965-4#article-info

U2 - 10.1038/s41467-024-52965-4

DO - 10.1038/s41467-024-52965-4

M3 - Journal article

C2 - 39362888

AN - SCOPUS:85205605276

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 8588

ER -

Targeting osteoblastic 11β-HSD1 to combat high-fat diet-induced bone loss and obesity

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