Abstract
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.
Highlights
The central nervous system (CNS) regulates activity of peripheral organs to control the internal state of the body has been referred to interoception as an emerging science (Chen et al, 2021)
We found that neuropeptide Y (NPY) expression in the hypothalamus was regulated by prostaglandin E2 (PGE2)/ EP4 ascending interoceptive signaling to balance bone and fat metabolism
To determine the skeletal interoception from femur to the hypothalamus, an anterograde multisynaptic tracer herpes simplex virus type 1 (HSV-1) H129-G4 was directly injected in the femur marrow in 3-month-old wild-type mice (Zeng et al, 2017), GFP labeled neurons in arcuate nucleus (ARC) area has been detected at 5 days post infection (Figure 1A)
Summary
The central nervous system (CNS) regulates activity of peripheral organs to control the internal state of the body has been referred to interoception as an emerging science (Chen et al, 2021). We have established that sensory nerves in the bone perceive the concentration changes of osteoblast-derived prostaglandin E2 (PGE2) to activate PGE2 receptor EP4 as ascending interoceptive signal to the hypothalamus. We have demonstrated that PGE2/EP4 ascending interoceptive signal downregulates sympathetic tone for osteoblastic bone formation to maintain bone homeostasis as descending interoceptive signal (Chen et al, 2019; Hu et al, 2020). This descending interoceptive signal regulates lineage commitment of mesenchymal stem/stromal cells (MSCs) between osteoblasts and
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