Abstract
Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in β and α cells. We then generated β-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic β and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, β cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.
Highlights
Growth hormone secretagogue receptor (GHS-R) is a seven-transmembrane G-proteincoupled receptor (GPCR) expressed in the pituitary, various brain regions, and some peripheral tissues [1,2,3,4,5,6]
Using the GHS-R reporter line (GhsrIRES-tauGFP Knock-In), we demonstrated that the Green Fluorescent Protein (GFP) protein, a surrogate of GHS-R, was co-expressed, with α and β cells in pancreatic islets
Using β-cell-specific GHSR-deleted mice (MIP-Cre/ERT;Ghsrf/f), we unequivocally demonstrated that GHS-R deficiency in β cells attenuated insulin secretion and improved insulin sensitivity
Summary
Growth hormone secretagogue receptor (GHS-R) is a seven-transmembrane G-proteincoupled receptor (GPCR) expressed in the pituitary, various brain regions, and some peripheral tissues [1,2,3,4,5,6]. Reports of GHSR-null mice by us and others indicated that GHS-R regulates the growth hormone secretion in the pituitary, gluconeogenesis and glycogenolysis in the liver, thermogenesis in the adipose tissues, and systemic insulin sensitivity [2,10,11,12]. Since GHS-R is expressed in brain regions controlling glucose sensing and in peripheral tissues regulating glucose production, uptake, and regulation, it is difficult to decipher the cell-autonomous effect of GHS-R in pancreatic β-cells using GHSR-null mice. Our study aimed to confirm the expression of GHS-R in pancreatic islets and determine the role of β cell GHS-R in glucose homeostasis. Using β-cell-specific GHSR-deleted mice (MIP-Cre/ERT;Ghsrf/f), we unequivocally demonstrated that GHS-R deficiency in β cells attenuated insulin secretion and improved insulin sensitivity
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