High Co-Expression of the Ghrelin and LEAP2 Receptor GHSR with Pancreatic Polypeptide in Mouse and Human Islets

Islets represent an important site of direct action of the hormone ghrelin, with expression of the ghrelin receptor (growth hormone secretagogue receptor; GHSR) having been localized variably to alpha-cells, beta-cells, and/or somatostatin (SST)-secreting delta-cells. To our knowledge, GHSR expression by pancreatic polypeptide (PP)-expressing gamma-cells has not been specifically investigated. Here, histochemical analyses of Ghsr-IRES-Cre X Cre-dependent ROSA26-YFP reporter mice showed 85% of GHSR-expressing islet cells co-express PP, 50% co-express SST, and 47% co-express PP + SST. Analysis of single-cell transcriptomic data from mouse pancreas revealed 95% of Ghsr-expressing cells co-express Ppy, 100% co-express Sst, and 95% co-express Ppy + Sst. This expression was restricted to gamma-cell and delta-cell clusters. Analysis of several single-cell human pancreatic transcriptome datasets revealed 59% of GHSR-expressing cells co-express PPY, 95% co-express SST, and 57% co-express PPY + SST. This expression was prominent in delta-cell and beta-cell clusters, also occurring in other clusters including gamma-cells and alpha-cells. GHSR expression levels were upregulated by type 2 diabetes mellitus in beta-cells. In mice, plasma PP positively correlated with fat mass and with plasma levels of the endogenous GHSR antagonist/inverse agonist LEAP2. Plasma PP also elevated upon LEAP2 and synthetic GHSR antagonist administration. These data suggest that in addition to delta-cells, beta-cells, and alpha-cells, PP-expressing pancreatic cells likely represent important direct targets for LEAP2 and/or ghrelin in both mice and humans.