Zhang Xiao, Majumdar Anurag, Kim Clara, Kleiboeker Brian, Magee Kristann L, Learman Brian S, Thomas Steven A, Lodhi Irfan J, MacDougald Ormond A, Scheller Erica L
Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA.
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.
bioRxiv. 2024 Jul 31:2024.07.30.605812. doi: 10.1101/2024.07.30.605812.
Several adipose depots, including constitutive bone marrow adipose tissue (cBMAT), resist conventional lipolytic cues, making them metabolically non-responsive. However, under starvation, wasting, or cachexia, the body can eventually catabolize these stable adipocytes through unknown mechanisms. To study this, we developed a mouse model of brain-evoked depletion of all fat, including cBMAT, independent of food intake. Genetic, surgical, and chemical approaches demonstrated that depletion of stable fat required adipose triglyceride lipase-dependent lipolysis but was independent of local nerves, the sympathetic nervous system, and catecholamines. Instead, concurrent hypoglycemia and hypoinsulinemia activated a potent catabolic state by suppressing lipid storage and increasing catecholamine-independent lipolysis via downregulation of cell-autonomous lipolytic inhibitors . This was also sufficient to delipidate classical adipose depots. Overall, this work defines unique adaptations of stable adipocytes to resist lipolysis in healthy states while isolating a potent neurosystemic pathway by which the body can rapidly catabolize all adipose tissues.
包括组成性骨髓脂肪组织（cBMAT）在内的多个脂肪库对传统的脂解信号有抗性，使其代谢不敏感。然而，在饥饿、消瘦或恶病质状态下，机体最终可通过未知机制分解这些稳定的脂肪细胞。为研究此现象，我们建立了一种小鼠模型，可在不依赖食物摄入的情况下，通过脑诱发耗尽所有脂肪，包括cBMAT。基因、手术和化学方法表明，稳定脂肪的耗尽需要依赖脂肪甘油三酯脂肪酶的脂解作用，但与局部神经、交感神经系统和儿茶酚胺无关。相反，并发的低血糖和低胰岛素血症通过抑制脂质储存和经由下调细胞自主脂解抑制剂增加不依赖儿茶酚胺的脂解作用，激活了一种有效的分解代谢状态。这也足以使经典脂肪库脱脂。总体而言，这项工作定义了稳定脂肪细胞在健康状态下抵抗脂解的独特适应性，同时分离出了一种有效的神经全身途径，机体可通过该途径快速分解所有脂肪组织。
