Editors' ChoiceMetabolism

Finding the decretin hormone

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Sci. Signal.  10 Feb 2015:
Vol. 8, Issue 363, pp. ec29
DOI: 10.1126/scisignal.aaa8672

As a master controller of glucose metabolism, insulin is a tightly regulated hormone. Several hormones, referred to as incretins, enhance insulin secretion in response to increased glucose; however, few endocrine hormones have been identified that reduce insulin secretion in response to prolonged starvation. Alfa et al. ectopically expressed selected starvation-regulated genes in Drosophila and identified CG8317, which the authors named limostatin (lst) for the Greek goddess of starvation, as one that caused phenotypes associated with insulin deficiency. The abundance of lst mRNA peaked in adult flies after 24 hours of starvation and was reduced by refeeding the flies carbohydrates, but not protein. The lst gene encodes a putative propeptide with a signal peptide (for secretion) and several dibasic cleavage sites. Two arginine residues in the dibasic cleavage sites were necessary for the insulin-deficiency phenotypes associated with overexpression. Flies with a P element insertion that eliminated lst (lst1) had phenotypes associated with excess insulin, such as hypoglycemia, obesity, and shortened lifespan, and these flies also had increased abundance of a tagged form of circulating insulin-like peptide 2 (Ilp2). Silencing the electrical activity of insulin-producing cells (IPCs, the fly equivalent of pancreatic β cells), which is necessary for Ilp secretion, eliminated differences in triglyceride content between control and lst1 flies. Analysis of flies expressing an lst promoter reporter indicated that Lst was produced by gut-associated endocrine cells that also produce an incretin hormone. Flies in which lst was knocked down in these cells had a similar phenotype as lst1 flies, and expression of lst specifically in those cells rescued the lst1 phenotype. Application of a 15-amino-acid peptide derived from Lst, Lst-15, inhibited calcium signals in and inhibited Ilp2 release from IPCs. Screening for genes encoding G protein–coupled receptors (GPCRs), which are commonly targets of peptide hormones, that exhibited increased expression in lst1 and decreased expression when lst was overexpressed identified CG9918. IPC-specific knockdown of CG9918 phenocopied lst1 and blocked the attenuating effect of Lst-15 on Ilp2 secretion from IPCs. The GPCRs most similar to CG9918 in mammals are the neuromedin U receptors (NMURs), and NMUR1 is found in the periphery. NMUR1 protein and mRNA were present in human pancreatic β cells and the gene encoding the ligand NMU was expressed in stomach and duodenum (human foregut, analogous to the cells in flies that produced Lst). Application of NMU-25 to human islets inhibited glucose-stimulated insulin release and a mutant form of NMU associated with obesity failed to suppress insulin release. Thus, Lst-15 and NMU-25 appear to function as endocrine decretin hormones.

R. W. Alfa, S. Park, K.-R. Skelly, G. Poffenberger, N. Jain, X. Gu, L. Kockel, J. Wang, Y. Liu, A. C. Powers, S. K. Kim, Suppression of insulin production and secretion by a decretin hormone. Cell Metab. 21, 323–333 (2015). [PubMed]