Ablation of Fat Cells in Adult Mice Induces Massive Bone Gain

Zou, Wei; Rohatgi, Nidhi; Brestoff, Jonathan R.; Li, Yongjia; Barve, Ruteja A.; Tycksen, Eric; Kim, Yung; Silva, Matthew J.; Teitelbaum, Steven L.

doi:10.1016/j.cmet.2020.09.011

Cited by 70 publications

(53 citation statements)

References 71 publications

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“…Furthermore, the dissociation of BM Adipsin from circulating levels in aging mice reinforces a paracrine function of Adipsin in the BM niche. Our findings help provide an explanation of a previous observation that changes in peripheral adipose tissues have minimal impact on osteogenesis ( Zou et al, 2020 ). Future investigations should note the distinction between Adipsin sourced from the BM and peripheral adipose tissue.…”

Section: Discussionsupporting

confidence: 82%

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

Aaron

Kraakman

Zhou

et al. 2021

eLife

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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).

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Section: Discussionsupporting

confidence: 82%

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

Aaron

Kraakman

Zhou

et al. 2021

eLife

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“…Furthermore, the dissociation of BM Adipsin from circulating levels in aging mice reinforces a paracrine function of Adipsin in the BM niche. Our findings help to provide an explanation of a previous observation that changes in peripheral adipose tissues have minimal impact on osteogenesis (63). Future investigations should note the distinction between Adipsin sourced from the BM and peripheral adipose tissue, such as developing an Adipsin floxed mouse model to specifically ablate Adipsin from the BM to examine the tissue-specific role of Adipsin.…”

Section: Discussionsupporting

confidence: 53%

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

Aaron

Kraakman

et al. 2021

Preprint

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Background: Bone marrow (BM) adipose tissue (BMAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the marrow niche. As a reflection of BM remodeling, BMAT is highly responsive to nutrient fluctuations, hormonal changes and metabolic disturbances such as obesity and diabetes mellitus. Expansion of BMAT 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: Using C57BL/6 mice as a model, we employed the bone-protected PPARg constitutive deacetylation (2KR), Adipsin, and its downstream effector, C3, knockout mice. These mice were challenged to thiazolidinedione treatment, calorie restriction, or aging in order to induce bone loss and MAT expansion. Analysis of bone 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 (BMSCs) 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 have shown that Adipsin is the most up-regulated adipokine during BMAT expansion in mice and humans, in a PPARg acetylation-dependent manner. Ablation of Adipsin in mice specifically inhibited BMAT 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/b-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), and P01HL087123 (LQ).

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“…The ability of BMAds to concurrently influence bone remodeling and hematopoiesis ( 7 , 8 ) places them in a crucial position in the regulation of bone and immune cell fate. Notably, recent evidence demonstrated that BMAds play a decisive role in regulating immune responses, contributing to increased levels of pro-inflammatory cytokines and oxidative stress ( 6 ).…”

Section: Discussionmentioning

confidence: 99%

“…As such, BMAds may participate in the immune response and tissue remodeling. In fact, BMAds have been recently shown to control bone remodeling and bone mass maintenance ( 7 , 8 ). In adulthood, BMAT can account for up to 70% of the bone marrow cavity, and it is further increased in diverse clinical conditions, including obesity, type 2 diabetes, anorexia, and osteoporosis ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Rodent Models of Spondyloarthritis Have Decreased White and Bone Marrow Adipose Tissue Depots

et al. 2021

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Bone marrow adipose tissue (BMAT) has recently been recognized as a distinct fat depot with endocrine functions. However, if and how it is regulated by chronic inflammation remains unknown. Here, we investigate the amount of white fat and BMAT in HLA-B27 transgenic rats and curdlan-challenged SKG mice, two well-established models of chronic inflammatory spondyloarthritis (SpA). Subcutaneous and gonadal white adipose tissue and BMAT was reduced by 65-70% and by up to 90% in both experimental models. Consistently, B27 rats had a 2-3-fold decrease in the serum concentrations of the adipocyte-derived cytokines adiponectin and leptin as well as a 2-fold lower concentration of triglycerides. The bone marrow of B27 rats was further characterized by higher numbers of neutrophils, lower numbers of erythroblast precursors, and higher numbers of IL-17 producing CD4+ T cells. IL-17 concentration was also increased in the serum of B27 rats. Using a cell culture model, we show that high levels of IL-17 in the serum of B27 rats negatively impacted adipogenesis (-76%), an effect that was reversed in the presence of neutralizing anti-IL-17 antibody. In summary, these findings show BMAT is severely reduced in two experimental models of chronic inflammatory SpA and suggest that IL-17 is involved in this process.

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Ablation of Fat Cells in Adult Mice Induces Massive Bone Gain

Cited by 70 publications

References 71 publications

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

Rodent Models of Spondyloarthritis Have Decreased White and Bone Marrow Adipose Tissue Depots

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