The dynamics of human bone marrow adipose tissue in response to feeding and fasting

Abstract

BACKGROUND Adipocytes were long considered inert components of the bone marrow niche, but mouse and human models suggest bone marrow adipose tissue (BMAT) is dynamic and responsive to hormonal and nutrient cues. METHODS In this study of healthy volunteers, we investigated how BMAT responds to acute nutrient changes, including analyses of endocrine determinants and paracrine factors from marrow aspirates. Study participants underwent a 10-day high-calorie protocol, followed by a 10-day fast. RESULTS We demonstrate (a) vertebral BMAT increased significantly during high-calorie feeding and fasting, suggesting BMAT may have different functions in states of caloric excess compared with caloric deprivation; (b) ghrelin, which decreased in response to high-calorie feeding and fasting, was inversely associated with changes in BMAT; and (c) in response to high-calorie feeding, resistin levels in the marrow sera, but not the circulation, rose significantly. In addition, TNF-α expression in marrow adipocytes increased with high-calorie feeding and decreased upon fasting. CONCLUSION High-calorie feeding, but not fasting, induces an immune response in bone marrow similar to what has been reported in peripheral adipose tissue. Understanding the immunomodulatory regulators in the marrow may provide further insight into the homeostatic function of this unique adipose tissue depot. FUNDING NIH grant R24 DK084970, Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH, award UL 1TR002541), and NIH grants P30 DK040561 and U19 AG060917S1.

Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits

“…Alternatively, it is possible that androgens increase energy requirements of bone such that male mice are more dependent on BMAd lipolysis under stressful conditions. Consistent with this tenet, in both mouse and human studies of calorie restriction, males tend to have greater induction of BMAds than females ( Fazeli et al, 2021 ). Importantly, we observed that bone volume fraction and trabecular number were increased by 12 weeks of CR in OVX mice of both genotypes, suggesting that the metabolic and anti-aging benefits of CR somehow block the bone loss associated with estrogen deficiency as mice aged to 40 weeks.…”

“…With the loss of peripheral WAT in CR mice, there is a dramatic increase in BMAT throughout the tibia, and this is accompanied by increased expression of adipocyte genes, including those involved in lipid uptake, de novo lipogenesis, and lipolysis. BMAT expansion with CR has been observed in both rodents and humans ( Cawthorn et al, 2014 ; Devlin et al, 2010 ; Fazeli et al, 2021 ), and mechanisms underlying this observation are still not fully understood. We speculate that CR promotes lipolysis in peripheral adipose tissues, and the released non-esterified fatty acids have increased flux to bone marrow, where they are used either directly to maintain hematopoiesis and bone homeostasis, or used indirectly after having been stored and released from BMAT.…”

Bone marrow adipose tissue composition and glycemic improvements after gastric bypass surgery

“…In addition there could be an independent effect of antidiabetic medication, although no participants were prescribed thiazolidinediones and there is not a clear relationship between other antidiabetic medication and marrow adiposity. Our follow-up was limited to six months, although a recent study has demonstrated that BMAT can dynamically respond after 10 days of a high calorie diet and 10 days of fasting ( Fazeli et al, 2021 ). Our modest sample size limits generalizability but provides hypothesis-generating data on the role of BMAT composition in diabetes.…”

Distinct Metabolism of Bone Marrow Adipocytes and their Role in Bone Metastasis

“…Here, mostly rBMAs localized in the metaphysis of the proximal tibia expand as response to changes in diet and diseases (11,12). The special location of fat induced expansion of BMAs was confirmed in humans suffering from obesity, diabetes and/or osteoporosis (13,14). In mice, irradiation and activation of the adipocyte differentiation pathway Peroxisome proliferator-activated receptor gamma (PPARg) leads to a steady induction of BMA expansion (15).…”

“…Additionally, expansion of BMAs can be observed in murine models of aging or ovariectomy-induced osteoporosis similar to the observations in patients ( 16 , 17 ). Intriguingly, caloric deprivation in patients also increases the number of BMAs with gender difference regarding their localization, in L4 vertebra for men and at the femoral metaphysis for women ( 13 ). In addition, the psychiatric disease anorexia nervosa paradoxically leads to expanded bone marrow adipose tissue, while other fat depots in the body are reduced in size ( 18 ).…”