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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 …