Abstract
Abstract Disclosure: X. Zhang: None. A. Majumdar: None. B. Kleiboeker: None. K.L. Magee: None. B.S. Learman: None. S.A. Thomas: None. I.J. Lodhi: None. O.A. MacDougald: None. E.L. Scheller: None. Adipocytes classically store or release energy in response to changes in metabolic status. However, several fat depots throughout the body are resistant to these metabolic cues. Identification of novel mechanisms that drive energy release from metabolically inert adipocytes is needed to inform strategies to deplete stubborn fat and, conversely, to preserve these depots in pathologic settings of wasting and cachexia. To address this question, we focused on the constitutive bone marrow adipose tissue (cBMAT), a well-established site of metabolically inert fat that remains unchanged with fasting, exercise, and cold exposure and is depleted only in certain extreme conditions such as cachexia or starvation. To study this unique depot, we developed a mouse model of rapid, complete depletion of all fat, including cBMAT, within 9 days using central intracerebroventricular (ICV) injection of leptin. Surgical denervation, chemical sympathectomy, or genetic dopamine beta-hydroxylase (DBH) deletion did not prevent the ICV leptin-induced depletion of cBMAT, revealing this process to be independent of catecholamines and the sympathetic nervous system (SNS). Vossicle implantation defined the mediators as transported through the circulation, and BMAT-specific ablation of adipose triglyceride lipase (ATGL) identified dependence on basal lipolysis. Gene expression and a radioisotope-based de novo lipogenesis assay pinpointed a concurrent suppression of lipogenesis, and subcutaneous insulin supplementation prevented leptin-induced cBMAT depletion, but not other depots. Together, this defines the differential regulation of metabolism in metabolically inert fat depots such as cBMAT. Specifically, leptin-responsive circuits in the brain can deplete inert adipocytes by suppressing lipogenesis while maintaining basal lipolysis independent of the SNS. Presentation: Saturday, June 17, 2023
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