Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells
Background: Marrow adipose tissue (MAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the bone marrow (BM) niche. As a reflection of BM remodeling, MAT is highly responsive to nutrient fluctuations, hormonal changes, and metabolic disturbances such as o...
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Language: | English |
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eLife Sciences Publications Ltd
2021-06-01
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Online Access: | https://elifesciences.org/articles/69209 |
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doaj-dafb113ceb224ac9aedae25c7e925dc7 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nicole Aaron Michael J Kraakman Qiuzhong Zhou Qiongming Liu Samantha Costa Jing Yang Longhua Liu Lexiang Yu Liheng Wang Ying He Lihong Fan Hiroyuki Hirakawa Lei Ding James Lo Weidong Wang Baohong Zhao Edward Guo Lei Sun Cliff J Rosen Li Qiang |
spellingShingle |
Nicole Aaron Michael J Kraakman Qiuzhong Zhou Qiongming Liu Samantha Costa Jing Yang Longhua Liu Lexiang Yu Liheng Wang Ying He Lihong Fan Hiroyuki Hirakawa Lei Ding James Lo Weidong Wang Baohong Zhao Edward Guo Lei Sun Cliff J Rosen Li Qiang Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells eLife adipsin bone marrow adiposity complement PPARgamma adipokine |
author_facet |
Nicole Aaron Michael J Kraakman Qiuzhong Zhou Qiongming Liu Samantha Costa Jing Yang Longhua Liu Lexiang Yu Liheng Wang Ying He Lihong Fan Hiroyuki Hirakawa Lei Ding James Lo Weidong Wang Baohong Zhao Edward Guo Lei Sun Cliff J Rosen Li Qiang |
author_sort |
Nicole Aaron |
title |
Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells |
title_short |
Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells |
title_full |
Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells |
title_fullStr |
Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells |
title_full_unstemmed |
Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells |
title_sort |
adipsin promotes bone marrow adiposity by priming mesenchymal stem cells |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2021-06-01 |
description |
Background: Marrow adipose tissue (MAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the bone marrow (BM) niche. As a reflection of BM remodeling, MAT is highly responsive to nutrient fluctuations, hormonal changes, and metabolic disturbances such as obesity and diabetes mellitus. Expansion of MAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling.
Methods: We studied deletion of Adipsin, and its downstream effector, C3, in C57BL/6 mice as well as the bone-protected PPARγ constitutive deacetylation 2KR mice to assess BM plasticity. The mice were challenged with thiazolidinedione treatment, calorie restriction, or aging to induce bone loss and MAT expansion. Analysis of bone mineral density and marrow adiposity was performed using a μCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high-calorie diet in healthy human volunteers.
Results: We show that Adipsin is the most upregulated adipokine during MAT expansion in mice and humans in a PPARγ acetylation-dependent manner. Genetic ablation of Adipsin in mice specifically inhibited MAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/β-catenin signaling.
Conclusions: Adipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine.
Funding: This work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), R24DK092759 (CJR), and P01HL087123 (LQ). |
topic |
adipsin bone marrow adiposity complement PPARgamma adipokine |
url |
https://elifesciences.org/articles/69209 |
work_keys_str_mv |
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doaj-dafb113ceb224ac9aedae25c7e925dc72021-06-22T11:30:31ZengeLife Sciences Publications LtdeLife2050-084X2021-06-011010.7554/eLife.69209Adipsin promotes bone marrow adiposity by priming mesenchymal stem cellsNicole Aaron0Michael J Kraakman1Qiuzhong Zhou2Qiongming Liu3Samantha Costa4Jing Yang5Longhua Liu6Lexiang Yu7Liheng Wang8Ying He9Lihong Fan10Hiroyuki Hirakawa11Lei Ding12https://orcid.org/0000-0003-4869-8877James Lo13Weidong Wang14Baohong Zhao15Edward Guo16Lei Sun17https://orcid.org/0000-0003-3937-941XCliff J Rosen18Li Qiang19https://orcid.org/0000-0001-8322-1797Naomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Pharmacology, Columbia University, New York, United StatesNaomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Medicine, Columbia University, New York, United StatesCardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, SingaporeNaomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Pathology and Cellular Biology, Columbia University, New York, United StatesCenter for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United States; School of Medicine, Tufts University, Boston, United States; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, United StatesNaomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Pathology and Cellular Biology, Columbia University, New York, United StatesNaomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Pathology and Cellular Biology, Columbia University, New York, United StatesNaomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Pathology and Cellular Biology, Columbia University, New York, United StatesNaomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Medicine, Columbia University, New York, United StatesNaomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Pathology and Cellular Biology, Columbia University, New York, United StatesNaomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Pathology and Cellular Biology, Columbia University, New York, United StatesDepartment of Microbiology and Immunology, Columbia University, New York, United States; Department of Rehabilitation and Regenerative Medicine, Vagelos College of Physicians and Surgeons, New York, United StatesDepartment of Microbiology and Immunology, Columbia University, New York, United States; Department of Rehabilitation and Regenerative Medicine, Vagelos College of Physicians and Surgeons, New York, United StatesWeill Center for Metabolic Health, Cardiovascular Research Institute, and Division of Cardiology, Weill Cornell Medical College, New York, United StatesDepartment of Medicine, Division of Endocrinology, Harold Hamm Diabetes Center, The University of Oklahoma Health Science Center, Oklahoma City, United StatesArthritis and Tissue Degeneration Program and The David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, Department of Medicine, Weill Cornell Medical College; Graduate Program in Cell & Developmental Biology, Weill Cornell Graduate School of Medical Sciences, New York, United StatesDepartment of Biomedical Engineering, Columbia University, New York, United StatesCardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, SingaporeCenter for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, United StatesNaomi Berrie Diabetes Cente, Columbia University, New York, United States; Department of Pathology and Cellular Biology, Columbia University, New York, United StatesBackground: Marrow adipose tissue (MAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the bone marrow (BM) niche. As a reflection of BM remodeling, MAT is highly responsive to nutrient fluctuations, hormonal changes, and metabolic disturbances such as obesity and diabetes mellitus. Expansion of MAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. Methods: We studied deletion of Adipsin, and its downstream effector, C3, in C57BL/6 mice as well as the bone-protected PPARγ constitutive deacetylation 2KR mice to assess BM plasticity. The mice were challenged with thiazolidinedione treatment, calorie restriction, or aging to induce bone loss and MAT expansion. Analysis of bone mineral density and marrow adiposity was performed using a μCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high-calorie diet in healthy human volunteers. Results: We show that Adipsin is the most upregulated adipokine during MAT expansion in mice and humans in a PPARγ acetylation-dependent manner. Genetic ablation of Adipsin in mice specifically inhibited MAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/β-catenin signaling. Conclusions: Adipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine. Funding: This work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), R24DK092759 (CJR), and P01HL087123 (LQ).https://elifesciences.org/articles/69209adipsinbone marrow adipositycomplementPPARgammaadipokine |