LepR‐Lineage 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 profile adipose populations and genetic lineage tracing to identify LepR-lineage stromal/progenitor cells contributing to cold-induced WAT browning. Ablation of these cells using LepR-Cre-inducible DTR transgenic mice resulted in a decrease in the percentage of UCP1+ cells under cold conditions. The WAT browning process is controlled by peripheral nociceptive nerve-derived calcitonin gene-related peptide (CGRP), which was associated with reduced WAT browning and loss of LepR-lineage cells during intermittent fasting (IF), but not during cold exposure. Local antagonist experiments targeting the transient receptor potential cation channels TRPV1 and TRPM8 were associated with opposing changes in CGRP immunoreactivity and WAT browning. These findings support a condition-dependent role for nociceptive CGRP signaling in WAT remodeling.