<p>Obesity is a complex disease driven by multiple factors, and a deeper understanding of its underlying mechanisms could enable the development of novel treatments. Based on our previous experimental studies, we have proposed a homeostatic mechanism regulating adiposity involving mechano-sensing of body weight by osteoblast-lineage cells in the lower extremities. However, the molecular mechanism underlying this proposed weight-sensing pathway remains to be elucidated. Recent studies have demonstrated that Piezo1-mediated mechano-sensing in osteoblast-lineage cells, as well as TrkA-dependent signaling, are essential for the normal bone anabolic response to high-intensity mechanical loading. We hypothesized that these pathways within bone may also contribute to the sensing of sustained increased weight loading, thereby influencing the homeostatic regulation of body weight. To test this hypothesis, we first established a high-fat diet-induced obesity mouse model with conditional deletion of Piezo1 in osteoblast-lineage cells. Our results demonstrate that the effect of increased weight loading, induced by implanted weights, on body weight reduction is partially dependent on Piezo1 expression in osteoblast lineage cells. Similarly, using a mouse model lacking functional TrkA signaling, we demonstrated that the response to increased weight loading on body weight reduction is partially dependent on functional TrkA signaling. In conclusion, we demonstrate that the effect of increased weight loading on body weight is at least partially dependent on Piezo1 expression in osteoblast-lineage cells and intact TrkA signaling. Based on these findings we propose that increased body weight, resulting from adiposity, may be sensed by osteoblast-lineage cells through Piezo1 activation and that intact TrkA function is necessary for the weight-reducing response to increased weight loading. This mechanosensory input may then initiate compensatory central pathways that reduce adiposity and body weight.</p>