Skeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY

eLife

Bo Hu¹  Peng Xue¹  Hao Chen¹  Xu Cao¹  Amit Jain¹  Tuo Peter Li¹  Mei Wan¹  Xiao Wang¹  Xiao Lv²  Feng Gao²  Zengwu Shao³ 

[1] Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States;Department of Orthopaedic Surgery, Institute of Cell Engineering, and Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, United States;Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;

关键词: skeleton interoception;    bone formation;    neuroendocrine;    hypothalamus;    neuropeptide y;    prostaglandin E2;    Mouse;   

DOI  :  10.7554/eLife.70324

来源: eLife Sciences Publications, Ltd

【 摘 要 】

The central nervous system regulates activity of peripheral organs through interoception. In our previous study, we have demonstrated that PGE2/EP4 skeleton interception regulate bone homeostasis. Here, we show that ascending skeleton interoceptive signaling downregulates expression of hypothalamic neuropeptide Y (NPY) and induce lipolysis of adipose tissue for osteoblastic bone formation. Specifically, the ascending skeleton interoceptive signaling induces expression of small heterodimer partner-interacting leucine zipper protein (SMILE) in the hypothalamus. SMILE binds to pCREB as a transcriptional heterodimer on Npy promoters to inhibit NPY expression. Knockout of EP4 in sensory nerve increases expression of NPY causing bone catabolism and fat anabolism. Importantly, inhibition of NPY Y1 receptor (Y1R) accelerated oxidation of free fatty acids in osteoblasts and rescued bone loss in AvilCre:Ptger4fl/fl mice. Thus, downregulation of hypothalamic NPY expression lipolyzes free fatty acids for anabolic bone formation through a neuroendocrine descending interoceptive regulation.

【 授权许可】

CC BY