Role of Endogenous Cortistatin in the Regulation of Ghrelin System Expression at Pancreatic Level under Normal and Obese Conditions

Abstract

Ghrelin-system components [native ghrelin, In1-ghrelin, Ghrelin-O-acyltransferase enzyme (GOAT) and receptors (GHS-Rs)] are expressed in a wide variety of tissues, including the pancreas, where they exert different biological actions including regulation of neuroendocrine secretions, food intake and pancreatic function. The expression of ghrelin system is regulated by metabolic conditions (fasting/obesity) and is associated with the progression of obesity and insulin resistance. Cortistatin (CORT), a neuropeptide able to activate GHS-R, has emerged as an additional link in gut-brain interplay. Indeed, we recently reported that male CORT deficient mice (cort−/−) are insulin-resistant and present a clear dysregulation in the stomach ghrelin-system. The present work was focused at analyzing the expression pattern of ghrelin-system components at pancreas level in cort−/− mice and their control littermates (cort +/+) under low- or high-fat diet. Our data reveal that all the ghrelin-system components are expressed at the mouse pancreatic level, where, interestingly, In1-ghrelin was expressed at higher levels than native-ghrelin. Thus, GOAT mRNA levels were significantly lower in cort−/− mice compared with controls while native ghrelin, In1-ghrelin and GHS-R transcript levels remained unaltered under normal metabolic conditions. Moreover, under obese condition, a significant increase in pancreatic expression of native-ghrelin, In1-ghrelin and GHS-R was observed in obese cort+/+ but not in cort−/− mice. Interestingly, insulin expression and release was elevated in obese cort+/+, while these changes were not observed in obese cort−/− mice. Altogether, our results indicate that the ghrelin-system expression is clearly regulated in the pancreas of cort+/+ and cort −/− under normal and/or obesity conditions suggesting that this system may play relevant roles in the endocrine pancreas. Most importantly, our data demonstrate, for the first time, that endogenous CORT is essential for the obesity-induced changes in insulin expression/secretion observed in mice, suggesting that CORT is a key regulatory component of the pancreatic function.

In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: Evidence from clinical, cellular and molecular parameters

“…Based on previous results showing that In1-ghrelin variant can promote features of aggressiveness in breast cancer [ 13 ] and pituitary tumor cells [ 16 ], and on the results of our study, which demonstrated that the expression of the In1-ghrelin variant is a valuable marker to classify patients according to prognosis, we further explored the functional role of In1-ghrelin in two NET cell models. In vitro data revealed that overexpression of In1-ghrelin enhanced features of aggressiveness in human NET cells (i.e.…”

“…Soon after the discovery of native ghrelin, a number of alternative ghrelin gene-derived peptides and mRNA splice variants were identified [ 9 , 14 ]. One of these splice forms, the In1-ghrelin variant, is also expressed in the GIT and pancreas [ 15 , 16 ]. In1-ghrelin peptide shares the initial 13 aa with native ghrelin, including the first 5-aa, which is the minimum sequence required for ghrelin acylation by GOAT and for binding and activation of GHSR1a [ 9 , 15 ].…”

“…native ghrelin, GHSR1a and GHSR1b) are expressed in various tumors including pituitary adenomas and breast and prostate cancer, thus suggesting a possible autocrine or paracrine role of ghrelin system in the pathogenesis of these tumors (for review see: [ 9 ]). In fact, our group recently described that the In1-ghrelin spliced variant could contribute to the pathogenesis of breast tumors and pituitary adenomas [ 13 , 16 ]. However, there is still limited and conflicting data available on the precise functional roles that play the different components of the ghrelin system in the patho-physiology of cancer development and progression.…”

Ghrelin gene products, receptors, and GOAT enzyme: biological and pathophysiological insight

“…Moreover, obestatin probably plays a relevant role in the promotion of human islet cell survival and b-cell functioning (Granata et al 2008). Recent observations have also suggested that other ghrelin gene-derived molecules could be present in the endocrine pancreas, as in the case of the In1-ghrelin variant (Chanclon et al 2013), where it might play a functional role, which merits further investigation.…”

Transcriptome analysis in blood cells from children reveals potential early biomarkers of metabolic alterations

“…In addition to their roles in the CNS, both peptides also regulate endocrine secretion. CORT has been shown to bind with high affinity to the ghrelin receptor (GHSR) and play important actions on pancreatic function (41). In islets isolated from C57BL6 mice, CORT action has been reported to reduce the glucose-stimulated insulin secretion (42).…”