期刊
CELL METABOLISM
卷 21, 期 2, 页码 323-333出版社
CELL PRESS
DOI: 10.1016/j.cmet.2015.01.006
关键词
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资金
- Paul and Daisy Soros Fellowships
- Stanford Bio-X Program fellowship
- Stanford VPUE award
- NIH [1S10OD01058001A1, DK89572, DK072473]
- Department of Veterans Affairs (Merit Review)
- JDRF
- Vanderbilt Diabetes Research and Training Center [DK20593]
- Snyder Foundation
- Elser Foundation
- Doolittle Trust
- Howard Hughes Medical Institute (HHMI)
Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet beta cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output.
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