LepR-mesenchymal stem cells represent the main target of the nociceptive CGRP pathway in white adipose tissue browning

Sympathetic innervation regulates white adipose tissue (WAT) browning; however, the roles of nociceptive neurons and their associated target cells remain unknown. Here, we used single-nucleus RNA-sequencing to identify leptin receptor (LepR)-mesenchymal stem cells (MSCs) exhibiting intense WAT browning during cold exposure. Ablation of these cells using LepR-Cre inducible DTR transgenic mice resulted in a decrease in UCP-1 + percentage under cold conditions. The WAT browning process is controlled by nociceptive nerve-secreted peripheral calcitonin gene-related peptides (CGRPs), which reduce WAT browning by eradicating the LepR-MSC population during fasting, but not during cold exposure. Transient receptor potential cation channels TRPV1 and TRPM8 play opposing roles in regulating CGRP release. TRPV1 stimulates release, suppressing WAT browning, while TRPM8 inhibits release, promoting WAT browning. Manipulating TRPV1 and TRPM8 signaling to inhibit or activate CGRP release enhanced or suppressed WAT browning, respectively. Identifying nociceptive CGRP-controlled LepR-MSCs provides insights into therapeutic strategies for obesity and metabolic disorders.