Innervation of thermogenic adipose tissue via a calsyntenin 3β–S100b axis

Abstract

Summary 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.

New insights into the secretory functions of brown adipose tissue

“…As mentioned earlier, NRG4 has recently been found to respond to the autocrine effects of brown adipocyte-secreted BMP8b. Notably, B M Spiegelman's team has recently identified a new brown adipocyte-secreted factor: the S100b protein, which promoted neurite outgrowth from sympathetic neurons at adipose depots (Zeng et al 2019). S100b does not contain a signalling peptide corresponding to standard secretion pathway; this may have hampered its identification as a batokine in previous studies.…”

The Zn2+ and Ca2+‐binding S100B and S100A1 proteins: beyond the myths

“…In differentiated oligodendrocyte cells, S100B shows strong nuclear accumulation and might contribute to cell survival by inhibiting the transcriptional activity of p53 linked to apoptosis (Deloulme et al ., ). Dual regulation and interplay between S100B and p53 in the commitment and differentiation of multipotent progenitor cells might also influence other developmental processes such as adipogenesis and osteogenesis where both S100B (Saito et al ., ; Zeng et al ., ) and p53 (Molchadsky et al ., ; Velletri et al ., ) have modulatory functions.…”

Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

“…A recent study from Spiegelman's group demonstrated that S100, a BAT-derived secretory protein, promotes SNS innervation into adipose tissue. However, it is not clear whether S100 exerts the neurotrophic effect on SNS by itself or needs to work with other neurotrophic factors 21 . Interestingly, a newly identified hepatokine Tsukushi (TSK) has been shown to suppress brown fat thermogenesis via down-regulating sympathetic innervation 58 .…”

“…Although extensive studies have been devoted to the role of neuronal network and diverse neural-endocrine pathways in the regulation of SNS activation 19,20 , much less is known about the role of SNS-targeted tissues (e.g., BAT and WAT) in regulating the development and activation of SNS. A recent study from Spiegelman's group demonstrated that S100, a BATderived secretory protein, promotes SNS innervation into adipose tissue 21 . However, the mechanism underlying the neurotrophic effect of S100 on SNS is not entirely clear.…”