Marrow adipose tissue (MAT) is a unique fat depot, located in the skeleton, that has the potential to contribute to both local and systemic metabolic processes. In this review we highlight several recent conceptual developments pertaining to the origin and function of MAT adipocytes; consider the relationship of MAT to beige, brown, and white adipose depots; explore MAT expansion and turnover in humans and rodents; and discuss future directions for MAT research in the context of endocrine function and metabolic disease. MAT has the potential to exert both local and systemic effects on metabolic homeostasis, skeletal remodeling, hematopoiesis, and development of bone metastases. The diversity of these functions highlights the breadth of MAT’s potential impact on health and disease.

Bone marrow adipose tissue (MAT) accounts for up to 70% of bone marrow volume in healthy adults and increases further in clinical conditions of altered skeletal or metabolic function. Perhaps most strikingly, and in stark contrast to white adipose tissue, MAT has been found to increase during caloric restriction (CR) in humans and many other species. Hypoleptinemia may drive MAT expansion during CR but this has not been demonstrated conclusively. Indeed, MAT formation and function are poorly understood; hence, the physiological and pathological roles of MAT remain elusive. We recently revealed that MAT contributes to hyperadiponectinemia and systemic adaptations to CR. To further these observations, we have now performed CR studies in rabbits to determine whether CR affects adiponectin production by MAT. Moderate or extensive CR decreased bone mass, white adipose tissue mass, and circulating leptin but, surprisingly, did not cause hyperadiponectinemia or MAT expansion. Although this unexpected finding limited our subsequent MAT characterization, it demonstrates that during CR, bone loss can occur independently of MAT expansion; increased MAT may be required for hyperadiponectinemia; and hypoleptinemia is not sufficient for MAT expansion. We further investigated this relationship in mice. In females, CR increased MAT without decreasing circulating leptin, suggesting that hypoleptinemia is also not necessary for MAT expansion. Finally, circulating glucocorticoids increased during CR in mice but not rabbits, suggesting that glucocorticoids might drive MAT expansion during CR. These observations provide insights into the causes and consequences of CR-associated MAT expansion, knowledge with potential relevance to health and disease.

ObjectiveInsulin signaling plays pivotal roles in the development and metabolism of many tissues and cell types. A previous study demonstrated that ablation of insulin receptor (IR) with aP2-Cre markedly reduced adipose tissues mass and protected mice from obesity. However, multiple studies have demonstrated widespread non-adipocyte recombination of floxed alleles in aP2-Cre mice. These findings underscore the need to re-evaluate the role of IR in adipocyte and systemic metabolism with a more adipose tissue-specific Cre mouse line.MethodsWe generated and phenotyped a new adipose tissue-specific IR mouse model using the adipose tissue-specific Adipoq-Cre line.ResultsHere we show that the Adipoq-Cre-mediated IR KO in mice leads to lipodystrophy and metabolic dysfunction, which is in stark contrast to the previous study. In contrast to white adipocytes, absence of insulin signaling does not affect development of marrow and brown adipocytes, but instead is required for lipid accumulation particularly for the marrow adipocytes. Lipodystrophic IR KO mice have profound insulin resistance, hyperglycemia, organomegaly, and impaired adipokine secretion.ConclusionsOur results demonstrate differential roles for insulin signaling for white, brown, and marrow adipocyte development and metabolic regulation.

The adipocyte-derived hormone adiponectin mediates beneficial cardiometabolic effects, and hypoadiponectinemia is a biomarker for increased metabolic and cardiovascular risk. Indeed, circulating adiponectin decreases in obesity and insulin-resistance, likely because of impaired production from white adipose tissue (WAT). Conversely, lean states such as caloric restriction (CR) are characterized by hyperadiponectinemia, even without increased adiponectin production from WAT. The reasons underlying this paradox have remained elusive, but our recent research suggests that CR-associated hyperadiponectinemia derives from an unexpected source: bone marrow adipose tissue (MAT). Herein, we elaborate on this surprising discovery, including further discussion of potential mechanisms influencing adiponectin production from MAT; additional evidence both for and against our conclusions; and observations suggesting that the relationship between MAT and adiponectin might extend beyond CR. While many questions remain, the burgeoning study of MAT promises to reveal further key insights into MAT biology, both as a source of adiponectin and beyond.