Nociceptive control of cold- and fasting-induced WAT browning in heterogeneous cell populations

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 the leptin receptor (LepR)-mesenchymal stem cells (MSCs) exhibiting intense WAT browning during cold exposure and undergoing apoptosis during fasting. This 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 channel subfamily V member 1 (TRPV1) and subfamily M member 8 (TRPM8) nociceptors stimulate and inhibit CGRP release, thereby suppressing and enhancing WAT browning, respectively. CGRP receptor- and co-receptor-positive tdTomato+ MSCs were located near the sinusoid in <em>LepR-Cre/tdTomato</em> mice. Activation and inhibition of nociceptive CGRP release via TRPM8 and TRPV1 signaling manipulation suppressed and enhanced WAT browning, respectively. Therefore, nociceptive CGRP-controlled perisinusoidal LepR-MSCs undergo WAT browning during cold exposure and fasting.