A novel skeletal-specific adipogenesis pathway defines key origins and adaptations of bone marrow adipocytes with age and disease

Abstract

SUMMARYBone marrow adipocytes (BMAs) accumulate with age and in diverse disease states. However, their age- and disease-specific origins and adaptations remain unclear, impairing our understanding of their context-specific endocrine functions and relationship with surrounding tissues. In this study, we identified a novel, bone marrow-specific adipogenesis pathway using the AdipoqCre+/DTA+ ‘fat free’ mouse (FF), a model in which Adipoq-Cre drives diphtheria toxin-induced cell death in all adiponectin-expressing cells. Adiponectin is highly expressed by BMAs, peripheral adipocytes, and a subset of bone marrow stromal progenitor cells with preadipocyte-like characteristics. Consistent with this, FF mice presented with uniform depletion of peripheral white and brown adipose tissues, in addition to loss of BMAs in canonical locations such as the tail vertebrae. However, unexpectedly, a distinctly localized subset of BMAs accumulated with age in FF mice in regions such as the femoral and tibial diaphysis that are generally devoid of bone marrow adipose tissue (BMAT). Ectopic BMAs in FF mice were defined by increased lipid storage and decreased expression of cytokines including hematopoietic support factor Cxcl12 and adipokines adiponectin, resistin, and adipsin. FF BMAs also displayed resistance to lipolytic stimuli including cold stress and β3-adrenergic agonist CL316,243. This was associated with reduced expression of adrenergic receptors and monoacylglycerol lipase. Global ablation of adiponectin-expressing cells regulated bone accrual in an age- and sex-dependent manner. High bone mass was present early in life and this was more pronounced in females. However, with age, both male and female FF mice had decreased cortical thickness and mineral content. In addition, unlike BMAs in healthy mice, expansion of ectopic BMAs in FF mice was inversely correlated with cortical bone volume fraction. Subcutaneous fat transplant and normalization of systemic metabolic parameters was sufficient to prevent ectopic BMA expansion in FF mice but did not prevent the initial onset of the high bone mass phenotype. Altogether, this defines a novel, secondary adipogenesis pathway that relies on recruitment of adiponectin-negative stromal progenitors. This pathway is unique to the bone marrow and is activated with age and in states of metabolic stress, resulting in expansion of BMAs specialized for lipid storage with compromised lipid mobilization and endocrine function within regions traditionally devoted to hematopoiesis. Our findings further distinguish BMAT from peripheral adipose tissues and contribute to our understanding of BMA origins and adaptation with age and disease.

The benefits of adipocyte metabolism in bone health and regeneration

“…Of note, cBMAT starts to appear during embryogenesis and/or in early childhood whereas the development of rBMAT is thought to occur later in life and during aging in particular (Li et al, 2018;Suchacki et al, 2020;Robles et al, 2021). The transplantation of red bone marrow to ectopic sites results in the formation of a hematopoietic bone marrow nodule at the site of transplantation.…”

Report From the 6th International Meeting on Bone Marrow Adiposity (BMA2020)

“…After this, Leilei Zhong presented new data that defines a stromal/ perivascular, adiponectin-expressing bone marrow adipocyte progenitor, termed the marrow adipogenic lineage precursor (MALP) and its role in the maintenance of the bone marrow vasculature (34,35). Last, Xiao Zhang showed that a unique population of maladapted bone marrow adipocytes was retained in an otherwise 'fat free' lipodystrophic mouse, revealing the existence of a bone-specific, compensatory adipogenesis pathway that is activated in states of metabolic stress (36). Overall, this session contributed to our understanding of the unique cellular origins of bone marrow adipocytes during development and metabolic disease, in addition to providing new information about the molecular signals regulating the maturation of committed pre-adipocytes within the bone marrow.…”