Not just fillers: the emerging role of bone marrow adipocytes in bone and bone marrow homeostasis

Bone marrow adipose tissue (BMAT) is a phylogenetically conserved fat depot occupying a substantial fraction of the medullary cavity in vertebrates, yet its functional significance has only recently begun to be appreciated. Long dismissed as an inert filler, BMAT is now recognized as a dynamic and metabolically active compartment participating in the regulation of bone remodeling and hematopoiesis. Bone marrow adipocytes (BMAds) originate from skeletal stem cells (SSCs) and are anatomically and functionally distinct from peripheral white adipocytes, exhibiting a unique lipid metabolism and reduced lipolytic responsiveness under basal conditions. Two spatially and functionally distinct BMAT subtypes, i.e. regulated (rBMAT) and constitutive (cBMAT), respond differently to physiological and pathological stimuli, including caloric restriction, cold exposure, irradiation, and disease. BMAT expands in conditions such as osteoporosis and aging, while contracting in the context of bone metastasis and hematological malignancies, underscoring its tight coupling to the marrow microenvironment. Mechanistically, BMAT regulates bone remodeling by expressing osteoclastogenic factors and through lipid-mediated paracrine signaling, and supports or restrains hematopoietic stem cells, depending on context and skeletal site, by secreting key molecules in the hematopoietic niche. Emerging evidence from genome-wide Mendelian randomization studies now establishes a causal link between elevated BMAT and osteoporosis risk in humans. In the oncological setting, BMAds fuel tumor cell metabolism, promote cancer cell migration and chemoresistance, and remodel the marrow niche to favor malignant progression. This article critically reviews the current understanding of BMAT biology, from its anatomical organization and developmental origins to its roles in skeletal and hematopoietic homeostasis.