High coexpression of the ghrelin and LEAP2 receptor GHSR with pancreatic polypeptide in mouse and human islets

Deepali Gupta, Georgina K.C. Dowsett, Bharath Kumar Mani, Kripa Shankar, Sherri Osborne-Lawrence, Nathan P. Metzger, Brian Y.H. Lam, Giles S.H. Yeo, Jeffrey M. Zigman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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×Cre-dependent ROSA26-yellow fluorescent protein (YFP) reporter mice showed 85% of GHSR-expressing islet cells coexpress PP, 50% coexpress SST, and 47% coexpress PP+SST. Analysis of single-cell transcriptomic data from mouse pancreas revealed 95% of Ghsr-expressing cells coexpress Ppy, 100% coexpress Sst, and 95% coexpress Ppy+Sst. This expression was restricted to gamma-cell and delta-cell clusters. Analysis of several single-cell human pancreatic transcriptome data sets revealed 59% of GHSR-expressing cells coexpress PPY, 95% coexpress SST, and 57% coexpress 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 on 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 both in mice and humans.

Original languageEnglish (US)
JournalEndocrinology
Volume162
Issue number10
DOIs
StatePublished - Oct 1 2021

Keywords

  • Ghrelin
  • GHSR
  • Islet
  • LEAP2
  • Pancreatic polypeptide

ASJC Scopus subject areas

  • Endocrinology

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