Objective: While expression of the ghrelin receptor, GHSR (growth hormone secretagogue receptor), by pancreatic islets has been investigated, data regarding the specific islet cell types that express GHSR are inconsistent and incomplete. For instance, transcriptomic studies indicate marked GHSR expression by somatostatin (SST)-secreting delta cells vs. little to no GHSR expression by alpha cells and beta cells, which contrasts studies suggesting direct actions of ghrelin on GHSRs expressed by alpha cells and beta cells. Also, to our knowledge, GHSR expression by pancreatic polypeptide (PP) cells has not previously been directly investigated. The aims of this study were to determine GHSR expression within the four principal islet endocrine cell types and the effects of ghrelin on circulating PP.
Methods: Ghsr-IRES-Cre mice, which express Cre recombinase directed by the GHSR promoter, crossed to Cre-dependent ROSA26-YFP reporter mice were used to histologically identify GHSR expression in islets. Double and triple labeling for YFP-immunoreactivity (IR) with insulin-IR, glucagon-IR, SST-IR, and/or PP-IR was performed to determine GHSR co-expression with islet hormones. Pharmacological manipulations were used to examine in vivo effects of acyl-ghrelin on plasma PP.
Results: Eighty-five % of YFP-IR cells expressed PP-IR, 50% expressed SST-IR, and none expressed insulin-IR or glucagon-IR. GHSR antagonist raised plasma PP in overnight-fasted C57BL/6N mice. However, acyl-ghrelin administration had no effect on plasma PP in C57BL/6N mice.
Conclusions: These results suggest that within mouse pancreatic islets, GHSR expression occurs most abundantly in PP cells and that pharmacologic blockade of ghrelin action raises plasma PP.
D. Gupta: None. B.K. Mani: None. K. Shankar: None. S. Osborne-Lawrence: None. N. Metzger: None. J.M. Zigman: Stock/Shareholder; Self; Medtronic.
Diana and Richard C. Strauss Professorship in Biomedical Research; Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine; Kent and Jodi Foster Distinguished Chair in Endocrinology; University of Texas Southwestern Medical Center (to J.M.Z.)