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Role of endogenous cortistatin in the regulation of ghrelin system expression at pancreatic level under normal and obese conditions.

Chanclón B, Luque RM, Córdoba-Chacón J, Gahete MD, Pozo-Salas AI, Castaño JP, Gracia-Navarro F, Martínez-Fuentes AJ - PLoS ONE (2013)

Bottom Line: Cortistatin (CORT), a neuropeptide able to activate GHS-R, has emerged as an additional link in gut-brain interplay.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Physiology and Immunology, University of Cordoba and Reina Sofia University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain.

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.

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Expression level of different ghrelin system components in the whole pancreas of cort+/+ and cort−/− male mice fed a low fat (LF) or high fat diet (HFD).Values represent mean ± SEM of copy number adjusted by normalization factor (NF) per 100 ng of cDNA obtained from 3–7 animals per experimental group. (*: p<0,05; **: p<0,01; ***: p<0,001).
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pone-0057834-g001: Expression level of different ghrelin system components in the whole pancreas of cort+/+ and cort−/− male mice fed a low fat (LF) or high fat diet (HFD).Values represent mean ± SEM of copy number adjusted by normalization factor (NF) per 100 ng of cDNA obtained from 3–7 animals per experimental group. (*: p<0,05; **: p<0,01; ***: p<0,001).

Mentions: Expression of ghrelin, In1-ghrelin variant, GHS-R and GOAT in the pancreas of cort+/+ and cort−/− mice were determined by qRT-PCR (Fig. 1). All components of the ghrelin system were expressed in pancreatic extracts of cort+/+ and cort−/− mice; however, their relative expression levels markedly differed. Interestingly, In1-ghrelin expression was substantially higher than that of ghrelin in cort+/+ mice (834.5±92.48 vs. 14.4±1.21 mRNA copies/NF per 100 ng total RNA, respectively; n = 5) as well as in cort−/− mice (1047.6±105.42 vs. 16.0±2.09 mRNA copies/NF per 100 ng total RNA, respectively; n = 4) (Fig. 1). Moreover, GOAT was highly expressed as compared to ghrelin (62.2±9.98 mRNA copies/NF per 100 ng total RNA), and GHS-R showed low expression levels in cort +/+ mice under LFD (21.1±3.65 mRNA copies/NF per 100 ng total RNA) (Fig. 1). Lack of CORT, did not alter the expression of neither ghrelin forms nor GHS-R but significantly decreased GOAT expression (32.3±3.53 mRNA copies/NF per 100 ng total RNA) (Fig. 1).


Role of endogenous cortistatin in the regulation of ghrelin system expression at pancreatic level under normal and obese conditions.

Chanclón B, Luque RM, Córdoba-Chacón J, Gahete MD, Pozo-Salas AI, Castaño JP, Gracia-Navarro F, Martínez-Fuentes AJ - PLoS ONE (2013)

Expression level of different ghrelin system components in the whole pancreas of cort+/+ and cort−/− male mice fed a low fat (LF) or high fat diet (HFD).Values represent mean ± SEM of copy number adjusted by normalization factor (NF) per 100 ng of cDNA obtained from 3–7 animals per experimental group. (*: p<0,05; **: p<0,01; ***: p<0,001).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585174&req=5

pone-0057834-g001: Expression level of different ghrelin system components in the whole pancreas of cort+/+ and cort−/− male mice fed a low fat (LF) or high fat diet (HFD).Values represent mean ± SEM of copy number adjusted by normalization factor (NF) per 100 ng of cDNA obtained from 3–7 animals per experimental group. (*: p<0,05; **: p<0,01; ***: p<0,001).
Mentions: Expression of ghrelin, In1-ghrelin variant, GHS-R and GOAT in the pancreas of cort+/+ and cort−/− mice were determined by qRT-PCR (Fig. 1). All components of the ghrelin system were expressed in pancreatic extracts of cort+/+ and cort−/− mice; however, their relative expression levels markedly differed. Interestingly, In1-ghrelin expression was substantially higher than that of ghrelin in cort+/+ mice (834.5±92.48 vs. 14.4±1.21 mRNA copies/NF per 100 ng total RNA, respectively; n = 5) as well as in cort−/− mice (1047.6±105.42 vs. 16.0±2.09 mRNA copies/NF per 100 ng total RNA, respectively; n = 4) (Fig. 1). Moreover, GOAT was highly expressed as compared to ghrelin (62.2±9.98 mRNA copies/NF per 100 ng total RNA), and GHS-R showed low expression levels in cort +/+ mice under LFD (21.1±3.65 mRNA copies/NF per 100 ng total RNA) (Fig. 1). Lack of CORT, did not alter the expression of neither ghrelin forms nor GHS-R but significantly decreased GOAT expression (32.3±3.53 mRNA copies/NF per 100 ng total RNA) (Fig. 1).

Bottom Line: Cortistatin (CORT), a neuropeptide able to activate GHS-R, has emerged as an additional link in gut-brain interplay.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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Physiology and Immunology, University of Cordoba and Reina Sofia University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), and CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain.

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.

Show MeSH
Related in: MedlinePlus