Brown adipose tissue-derived extracellular vesicles regulate hepatocyte mitochondrial activity to alleviate high-fat diet-induced jawbone osteoporosis in mice
BackgroundLipid metabolic disorder (LMD) serves as a systemic driver of osteoporosis (OP), with jawbone osteoporosis (JOP) representing a clinically significant yet underexplored complication. Current clinical treatments for JOP remain suboptimal, highlighting the need for innovative approaches. The...
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Frontiers Media S.A.
2025-04-01
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| Series: | Frontiers in Endocrinology |
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| author | Kai Zhang Kai Zhang Sha Zhang Sha Zhang Sha Zhang Guorong Deng Guangxiang He Guangxiang He Yuan Yuan Yu Fu Yihan Liu Zhen Gong Liang Kong Chenxi Zheng |
| author_facet | Kai Zhang Kai Zhang Sha Zhang Sha Zhang Sha Zhang Guorong Deng Guangxiang He Guangxiang He Yuan Yuan Yu Fu Yihan Liu Zhen Gong Liang Kong Chenxi Zheng |
| author_sort | Kai Zhang |
| collection | DOAJ |
| description | BackgroundLipid metabolic disorder (LMD) serves as a systemic driver of osteoporosis (OP), with jawbone osteoporosis (JOP) representing a clinically significant yet underexplored complication. Current clinical treatments for JOP remain suboptimal, highlighting the need for innovative approaches. The use of metabolic regulators represents a promising therapeutic strategy for OP management. While brown adipose tissue-derived extracellular vesicles (BEV) exhibit metabolic regulatory potential, their capacity to mitigate LMD-associated OP remains unclear.MethodsA high-fat diet (HFD)-induced LMD mouse model was established to identify the JOP phenotype through micro-computed tomography (micro-CT) and transcriptomic profiling. BEV isolation was optimized using liberase enzyme-enhanced differential centrifugation, with in vivo tracking confirming biodistribution. In vitro, BEV effects on hepatocytes were assessed with triglyceride (TG) content, free fatty acid (FFA) levels, and mitochondrial function. The additional benefits of BEV on the osteogenic microenvironment were evaluated via AML12/MC3T3-E1 indirect co-culture under high-lipid conditions. Dual therapeutic effects of BEV on LMD and JOP in vivo were validated through metabolic phenotyping, micro-CT and histomorphometry analysis.ResultsSixteen weeks of HFD successfully induced typical LMD and JOP manifestations in mice. Transcriptomic sequencing revealed downregulation of osteogenic-related genes concomitant with upregulation of lipid metabolism-associated genes in the jawbone of LMD mice. In vivo tracking showed the exogenous BEV predominantly accumulated in the liver rather than the jawbone. BEV treatment significantly reduced intracellular TG and FFA content in hepatocytes, while enhancing osteogenic activity of MC3T3-E1 cells through indirect co-culture. Mitochondrial analyses revealed that BEV effectively increased the proportion of active mitochondria, reduced reactive oxygen species (ROS) generation rate, and enhanced oxygen consumption rate (OCR) in hepatocytes. Biochemical assay and metabolic cage testing showed a lower systemic lipid content level along with improved fat utilization and thermogenesis capacity in BEV-treated mice. Micro-CT and immunofluorescence staining further confirm significant improvements in the jawbone of BEV-treated mice regarding bone volume fraction, trabecular number, trabecular thickness, trabecular separation, and RUNX2 expression.ConclusionThis study establishes LMD as a crucial driver factor in JOP and identifies BEV-mediated mitochondrial transferring in hepatocytes as a therapeutic strategy for LMD-related JOP. |
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| publishDate | 2025-04-01 |
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| spelling | doaj-art-f6bc8c095bba40a9ba9c2f9dfbfbe1d72025-08-20T02:12:37ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-04-011610.3389/fendo.2025.15834081583408Brown adipose tissue-derived extracellular vesicles regulate hepatocyte mitochondrial activity to alleviate high-fat diet-induced jawbone osteoporosis in miceKai Zhang0Kai Zhang1Sha Zhang2Sha Zhang3Sha Zhang4Guorong Deng5Guangxiang He6Guangxiang He7Yuan Yuan8Yu Fu9Yihan Liu10Zhen Gong11Liang Kong12Chenxi Zheng13State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, ChinaState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi’an, ChinaState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, ChinaCollege of Basic Medicine, Shaanxi Key Laboratory of Research on TCM Physical Constitution and Diseases Prevention and Treatment, Shaanxi University of Chinese Medicine, Xianyang, ChinaDepartment of Traditional Chinese Medicine, The First Affiliated Hospital of Fourth Military Medical University, Xi’an, ChinaDepartment of Critical Care Medicine, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, ChinaThe First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, ChinaState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, ChinaState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, ChinaDepartment of Stomatology, The First Medical Center, Chinese Chinese PLA General Hospital, Beijing, ChinaAnalysis & Testing Laboratory for Life Sciences and Medicine of Fourth Military Medical University, Xi’an, ChinaState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi’an, ChinaState Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi’an, ChinaBackgroundLipid metabolic disorder (LMD) serves as a systemic driver of osteoporosis (OP), with jawbone osteoporosis (JOP) representing a clinically significant yet underexplored complication. Current clinical treatments for JOP remain suboptimal, highlighting the need for innovative approaches. The use of metabolic regulators represents a promising therapeutic strategy for OP management. While brown adipose tissue-derived extracellular vesicles (BEV) exhibit metabolic regulatory potential, their capacity to mitigate LMD-associated OP remains unclear.MethodsA high-fat diet (HFD)-induced LMD mouse model was established to identify the JOP phenotype through micro-computed tomography (micro-CT) and transcriptomic profiling. BEV isolation was optimized using liberase enzyme-enhanced differential centrifugation, with in vivo tracking confirming biodistribution. In vitro, BEV effects on hepatocytes were assessed with triglyceride (TG) content, free fatty acid (FFA) levels, and mitochondrial function. The additional benefits of BEV on the osteogenic microenvironment were evaluated via AML12/MC3T3-E1 indirect co-culture under high-lipid conditions. Dual therapeutic effects of BEV on LMD and JOP in vivo were validated through metabolic phenotyping, micro-CT and histomorphometry analysis.ResultsSixteen weeks of HFD successfully induced typical LMD and JOP manifestations in mice. Transcriptomic sequencing revealed downregulation of osteogenic-related genes concomitant with upregulation of lipid metabolism-associated genes in the jawbone of LMD mice. In vivo tracking showed the exogenous BEV predominantly accumulated in the liver rather than the jawbone. BEV treatment significantly reduced intracellular TG and FFA content in hepatocytes, while enhancing osteogenic activity of MC3T3-E1 cells through indirect co-culture. Mitochondrial analyses revealed that BEV effectively increased the proportion of active mitochondria, reduced reactive oxygen species (ROS) generation rate, and enhanced oxygen consumption rate (OCR) in hepatocytes. Biochemical assay and metabolic cage testing showed a lower systemic lipid content level along with improved fat utilization and thermogenesis capacity in BEV-treated mice. Micro-CT and immunofluorescence staining further confirm significant improvements in the jawbone of BEV-treated mice regarding bone volume fraction, trabecular number, trabecular thickness, trabecular separation, and RUNX2 expression.ConclusionThis study establishes LMD as a crucial driver factor in JOP and identifies BEV-mediated mitochondrial transferring in hepatocytes as a therapeutic strategy for LMD-related JOP.https://www.frontiersin.org/articles/10.3389/fendo.2025.1583408/fulllipid metabolic disorderjawbone osteoporosisbrown adipose tissueextracellular vesiclesmitochondrial activityosteogenic microenvironment |
| spellingShingle | Kai Zhang Kai Zhang Sha Zhang Sha Zhang Sha Zhang Guorong Deng Guangxiang He Guangxiang He Yuan Yuan Yu Fu Yihan Liu Zhen Gong Liang Kong Chenxi Zheng Brown adipose tissue-derived extracellular vesicles regulate hepatocyte mitochondrial activity to alleviate high-fat diet-induced jawbone osteoporosis in mice Frontiers in Endocrinology lipid metabolic disorder jawbone osteoporosis brown adipose tissue extracellular vesicles mitochondrial activity osteogenic microenvironment |
| title | Brown adipose tissue-derived extracellular vesicles regulate hepatocyte mitochondrial activity to alleviate high-fat diet-induced jawbone osteoporosis in mice |
| title_full | Brown adipose tissue-derived extracellular vesicles regulate hepatocyte mitochondrial activity to alleviate high-fat diet-induced jawbone osteoporosis in mice |
| title_fullStr | Brown adipose tissue-derived extracellular vesicles regulate hepatocyte mitochondrial activity to alleviate high-fat diet-induced jawbone osteoporosis in mice |
| title_full_unstemmed | Brown adipose tissue-derived extracellular vesicles regulate hepatocyte mitochondrial activity to alleviate high-fat diet-induced jawbone osteoporosis in mice |
| title_short | Brown adipose tissue-derived extracellular vesicles regulate hepatocyte mitochondrial activity to alleviate high-fat diet-induced jawbone osteoporosis in mice |
| title_sort | brown adipose tissue derived extracellular vesicles regulate hepatocyte mitochondrial activity to alleviate high fat diet induced jawbone osteoporosis in mice |
| topic | lipid metabolic disorder jawbone osteoporosis brown adipose tissue extracellular vesicles mitochondrial activity osteogenic microenvironment |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2025.1583408/full |
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