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

TitleA Secreted Slit2 Fragment Regulates Adipose Tissue Thermogenesis and Metabolic Function.
Publication TypeJournal Article
Year of Publication2016
AuthorsSvensson, KJ, Long, JZ, Jedrychowski, MP, Cohen, P, Lo, JC, Serag, S, Kir, S, Shinoda, K, Tartaglia, JA, Rao, RR, Chédotal, A, Kajimura, S, Gygi, SP, Spiegelman, BM
JournalCell Metab
Volume23
Issue3
Pagination454-66
Date Published2016 Mar 08
ISSN1932-7420
KeywordsAdipocytes, Beige, Adipose Tissue, White, Amino Acid Sequence, Animals, Cells, Cultured, Cyclic AMP-Dependent Protein Kinases, Energy Metabolism, Glucose, Homeostasis, Intercellular Signaling Peptides and Proteins, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Peptide Fragments, Signal Transduction, Thermogenesis
Abstract

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.

DOI10.1016/j.cmet.2016.01.008
Alternate JournalCell Metab.
PubMed ID26876562
PubMed Central IDPMC4785066
Grant ListP30 DK020541 / DK / NIDDK NIH HHS / United States
R37 DK031405 / DK / NIDDK NIH HHS / United States
R01 DK031405 / DK / NIDDK NIH HHS / United States
K99 DK105203 / DK / NIDDK NIH HHS / United States
DK031405 / DK / NIDDK NIH HHS / United States