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Cell Metab. 2016 Mar 8;23(3):454-66. doi: 10.1016/j.cmet.2016.01.008. Epub 2016 Feb 11.

A Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function.

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Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Laboratory of Molecular Metabolism, Rockefeller University, New York, NY 10065, USA.
Metabolic Health Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Sorbonne Universités, UPMC Paris 06, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Electronic address:


Activation of brown and beige fat can reduce obesity and improve glucose homeostasis through nonshivering thermogenesis. Whether brown or beige fat also secretes paracrine or endocrine factors to promote and amplify adaptive thermogenesis is not fully explored. Here we identify Slit2, a 180 kDa member of the Slit extracellular protein family, as a PRDM16-regulated secreted factor from beige fat cells. In isolated cells and in mice, full-length Slit2 is cleaved to generate several smaller fragments, and we identify an active thermogenic moiety as the C-terminal fragment. This Slit2-C fragment of 50 kDa promotes adipose thermogenesis, augments energy expenditure, and improves glucose homeostasis in vivo. Mechanistically, Slit2 induces a robust activation of PKA signaling, which is required for its prothermogenic activity. Our findings establish a previously unknown peripheral role for Slit2 as a beige fat secreted factor that has therapeutic potential for the treatment of obesity and related metabolic disorders.

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