Fig. 9. The working model of the mechanism by which Lepr⁺ cells modulate ISCs under conditions of HFD regime, fasting regime and post-irradiation.

Lepr⁺ cells are identified as a mesenchymal niche source for ISCs, and they can sense diet alterations to modulate ISCs via a stromal IGF1–epithelial IGF1R axis. Upon fasting, the abundance of Lepr⁺ cells dramatically decreases due to the reduced Leptin, leading to the reduction of Lepr⁺ cell-secreted Igf1. Consequently, the proliferation of ISCs and progenitor cells declines under fasting regime. Conversely, the abundance of Lepr⁺ cells increases upon HFD regime and post-irradiation, and the increased Lepr⁺ cells promote the proliferation of ISCs and progenitor cells by enhancing the secretion of Igf1.