Marrow adipocytes modify the neural regulation of bone

Bone marrow adipose tissue (BMAT) is a heterogenous and understudied adipose depot that fills approximately 70% of the adult human skeleton. Despite its abundance, the regulatory mechanisms and functional roles of bone marrow adipocytes (BMAds) remain poorly understood, particularly in the context of constitutive BMAd catabolism and its implications for skeletal health. The overall goal of this project is to define the neuro-adipose-bone crosstalk within the cBMAd-containing skeletal niche to promote the design and implementation of novel strategies to support bone health. Our central hypothesis is that activation of adaptive cBMAd lipolysis drives transcriptional remodeling to support anabolic cBMAd-osteoblast coupling in states of high sympathetic tone and neurosystemic stress, providing localized protection against age- and disease- associated bone loss. To test this hypothesis, we propose two specific aims. Aim 1 will define the mechanisms of cBMAd-mediated anabolism and bone protection and explore conservation in aged/post-menopausal states while creating new bioinformatic-based digital twin models that will inform personalized strategies to preserve skeletal integrity by computationally modeling cBMAd responses to physiological and pathological stress. Aim 2 will isolate the fate of catabolized cBMAds, quantify the changes in bone and muscle that occur after complete cBMAd loss while clarifying potential for recovery, and determine the lifespan and differentiation potential of cBMAds in vivo. This moves beyond established pathways to define mechanisms underlying the local role of cBMAds in the mitigation of the bone suppressive effects of high sympathetic tone. In addition to informing therapies to support healthy skeletal aging, this research has important implications for prevention of bone loss and fracture in diverse forms of wasting and cachexia and will support the development of new treatments to increase and preserve bone mass in settings of neurosystemic stress. Project Number: 1R01AG101404-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Erica Scheller | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $518,372 | Activity Code: R01 | Study Section: Skeletal Biology Development and Disease Study Section[SBDD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366255