TY - JOUR
T1 - Innervation of thermogenic adipose tissue via a calsyntenin 3β–S100b axis
AU - Zeng, Xing
AU - Ye, Mengchen
AU - Resch, Jon M.
AU - Jedrychowski, Mark P.
AU - Hu, Bo
AU - Lowell, Bradford B.
AU - Ginty, David D.
AU - Spiegelman, Bruce M.
N1 - Funding Information:
Acknowledgements We thank Nikon Imaging Center at Harvard Medical School for all imaging studies; RIKEN Institute for sharing the S100b knockout strain; Z. Herbert and the Molecular Biology Core Facilities at Dana Farber Cancer Institute for sequencing studies; the Rodent Histology Core at Harvard Medical School for histology studies; the EM Core at Harvard Medical School for APEX2 imaging studies; the viral core at Children’s Hospital Boston for AAV production; the transgenic core at Beth Israel Deaconess Medical Center for generation of mouse models; Y. Zhu for advice on sequencing data analysis. X.Z. was supported by the American Heart Association postdoctoral fellowship. B.H. is a Cancer Research Institute/Leonard Kahn Foundation Fellow. D.D.G. is an investigator of the Howard Hughes Medical Institute. This study was supported by NIH grant DK31405 to B.M.S.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/5/9
Y1 - 2019/5/9
N2 - The sympathetic nervous system drives brown and beige adipocyte thermogenesis through the release of noradrenaline from local axons. However, the molecular basis of higher levels of sympathetic innervation of thermogenic fat, compared to white fat, has remained unknown. Here we show that thermogenic adipocytes express a previously unknown, mammal-specific protein of the endoplasmic reticulum that we term calsyntenin 3β. Genetic loss or gain of expression of calsyntenin 3β in adipocytes reduces or enhances functional sympathetic innervation, respectively, in adipose tissue. Ablation of calsyntenin 3β predisposes mice on a high-fat diet to obesity. Mechanistically, calsyntenin 3β promotes endoplasmic-reticulum localization and secretion of S100b—a protein that lacks a signal peptide—from brown adipocytes. S100b stimulates neurite outgrowth from sympathetic neurons in vitro. A deficiency of S100b phenocopies deficiency of calsyntenin 3β, and forced expression of S100b in brown adipocytes rescues the defective sympathetic innervation that is caused by ablation of calsyntenin 3β. Our data reveal a mammal-specific mechanism of communication between thermogenic adipocytes and sympathetic neurons.
AB - The sympathetic nervous system drives brown and beige adipocyte thermogenesis through the release of noradrenaline from local axons. However, the molecular basis of higher levels of sympathetic innervation of thermogenic fat, compared to white fat, has remained unknown. Here we show that thermogenic adipocytes express a previously unknown, mammal-specific protein of the endoplasmic reticulum that we term calsyntenin 3β. Genetic loss or gain of expression of calsyntenin 3β in adipocytes reduces or enhances functional sympathetic innervation, respectively, in adipose tissue. Ablation of calsyntenin 3β predisposes mice on a high-fat diet to obesity. Mechanistically, calsyntenin 3β promotes endoplasmic-reticulum localization and secretion of S100b—a protein that lacks a signal peptide—from brown adipocytes. S100b stimulates neurite outgrowth from sympathetic neurons in vitro. A deficiency of S100b phenocopies deficiency of calsyntenin 3β, and forced expression of S100b in brown adipocytes rescues the defective sympathetic innervation that is caused by ablation of calsyntenin 3β. Our data reveal a mammal-specific mechanism of communication between thermogenic adipocytes and sympathetic neurons.
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U2 - 10.1038/s41586-019-1156-9
DO - 10.1038/s41586-019-1156-9
M3 - Article
C2 - 31043739
AN - SCOPUS:85065195772
VL - 569
SP - 229
EP - 235
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7755
ER -