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Nature. 2019 May;569(7755):229-235. doi: 10.1038/s41586-019-1156-9. Epub 2019 May 1.

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

Author information

1
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA.
2
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
3
Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.
4
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
5
Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
6
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA. bruce_spiegelman@dfci.harvard.edu.
7
Department of Cell Biology, Harvard Medical School, Boston, MA, USA. bruce_spiegelman@dfci.harvard.edu.

Abstract

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.

PMID:
31043739
PMCID:
PMC6589139
[Available on 2019-11-01]
DOI:
10.1038/s41586-019-1156-9

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