Schwann cells regulate brown adipose tissue innervation and remodeling through MEK/ERK signaling axis

Brown Adipose Tissue (BAT) is driven by neural innervation for thermogenesis and represents a potential therapeutic target for human obesity. However, the regulation mechanisms of BAT's neural innervation are still unclear. In this study, we validate the terminal regulation mechanism of BAT's neural innervation in which Schwann cells (SCs) control the neural innervation and remodeling of BAT by regulating the distribution of nerve endings. We found that specific ablation of Olfm4 in brown adipocytes instigates an abnormal dedifferentiation and atrophy of mature SCs, which is mediated by the activation of the MEK/ERK signaling axis. This atrophy results in a decrease in the distribution of myelinated sensory and unmyelinated sympathetic nerve endings, leading to a reduction in BAT's neural innervation and thermogenic impairment. Consequently, mice exhibit heightened sensitivity to cold and diet-induced obesity. Notably, the application of a MEK/ERK inhibitor reverses this abnormal dedifferentiation of SCs, rescuing these phenotypes. In addition, our study describes the profound remodeling process that SCs undergo in response to temperature changes, wherein SCs experience reversible dedifferentiation in response to thermal neutrality or mild cold exposure, thus modulating the remodeling of the BAT neural network. Importantly, inhibition of MEK/ERK blocks this dedifferentiation of SCs, reversing thermal neutrality-induced BAT remodeling, thereby reinforcing the central role of SCs in the complex cellular response during temperature-induced BAT remodeling. In conclusion, our study confirms the crucial regulatory role of SCs in the neural innervation and remodeling process of BAT, offering novel insights for the activation of BAT to treat obesity. To study the function of OLFM4 in BAT, we crossed Olfm4 flox/flox mice with Ucp1-Cre mice to construct brown adipocyte-specific knockout mice (Ucp1-Cre; Olfm4 flox/flox, Olfm4CKO) for Olfm4To investigate the effect of Olfm4 ablation on BAT, we employed RNA sequencing (RNA-Seq) to analyze the interscapular BAT (iBAT) of Olfm4CKO and Ctrl mice.