Innervation of Thermogenic Adipose Tissue via a Calsyntenin-3β/S100b Axis

The sympathetic nervous system drives brown and beige adipocyte thermogenesis via release of norepinephrine from local axons. However, the molecular basis underlying the higher levels of sympathetic innervation of thermogenic fat, compared to white fat, has remained elusive. Here we show that thermogenic adipocytes express a previously unknown, mammal-specific endoplasmic reticulum membrane protein, termed Calsyntenin-3β. Genetic loss or gain of Calsyntenin-3β in adipocytes reduces or enhances functional sympathetic innervation in adipose tissue respectively; Calsyntenin-3β ablation predisposes mice to obesity on a high fat diet. Mechanistically, Calsyntenin-3β promotes endoplasmic reticulum localization and secretion from brown adipocytes of S100b, a protein lacking a signal peptide. S100b stimulates neurite outgrowth from sympathetic neurons in vitro. S100b deficiency phenocopies Calsyntenin-3β deficiency, whereas forced expression of S100b in brown adipocytes rescues defective sympathetic innervation caused by Calsyntenin-3β ablation. Taken together, our data elucidate a mammal-specific mechanism of communication between thermogenic adipocytes and sympathetic neurons.