Proghrelin peptides: Desacyl ghrelin is a powerful inhibitor of acylated ghrelin, likely to impair physiological effects of acyl ghrelin but not of obestatin

Objective: To investigate the efficacy of dietary supplementation of medium-chain triglycerides (MCTs) and its effects on ghrelin activation in healthy adults. Methods: The present study examined two protocols with six healthy volunteers: 1) 12-hour profiles of the plasma levels of acylated and desacyl ghrelin without MCT ingestion, and 2) changes in serum ghrelin levels after oral ingestion of 45 g/day of MCTs for 1 week. Results: At baseline, serum acylated and desacyl ghrelin levels were 18.2±10.3 and 77.1±23.4 fmol/mL, respectively. The ratio of acylated/desacyl ghrelin was 19%. There were no significant differences in the 12-hour profiles of acylated and desacyl ghrelin. Significant increases were observed in all sampling times of serum acylated ghrelin after 1-week MCTs ingestion. The ratio of acylated/desacyl ghrelin increased to 37.7%. Conclusions: Oral ingestion of MCTs increased serum acylated ghrelin levels in healthy adults, suggesting that MCTs administration stimulates food intake.

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Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin

Gut ◽

10.1136/gut.2004.038737 ◽

2005 ◽

Vol 54 (1) ◽

pp. 18-24 ◽

Cited By ~ 322

Author(s):

A Asakawa

Keyword(s):

Energy Balance ◽

Acylated Ghrelin ◽

Desacyl Ghrelin

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Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels?

Acta Endocrinologica ◽

10.1530/eje-13-0347 ◽

2014 ◽

Vol 170 (6) ◽

pp. 799-807 ◽

Cited By ~ 40

Author(s):

Behiye Özcan ◽

Sebastian J C M M Neggers ◽

Anne Reifel Miller ◽

Hsiu-Chiung Yang ◽

Virginia Lucaites ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Glycemic Control ◽

Postprandial Glucose ◽

Acylated Ghrelin ◽

Double Blind ◽

Glucose Levels ◽

Acyl Ghrelin ◽

Standard Breakfast

ObjectiveThe objective of this study was to assess the effects of a continuous overnight infusion of des-acyl ghrelin (DAG) on acylated ghrelin (AG) levels and glucose and insulin responses to a standard breakfast meal (SBM) in eight overweight patients with type 2 diabetes. Furthermore, in the same patients and two additional subjects, the effects of DAG infusion on AG concentrations and insulin sensitivity during a hyperinsulinemic–euglycemic clamp (HEC) were assessed.Research design and methodsA double-blind, placebo-controlled cross-over study design was implemented, using overnight continuous infusions of 3 and 10 μg DAG/kg per h and placebo to study the effects on a SBM. During a HEC, we studied the insulin sensitivity.ResultsWe observed that, compared with placebo, overnight DAG administration significantly decreased postprandial glucose levels, both during continuous glucose monitoring and at peak serum glucose levels. The degree of improvement in glycemia was correlated with baseline plasma AG concentrations. Concurrently, DAG infusion significantly decreased fasting and postprandial AG levels. During the HEC, 2.5 h of DAG infusion markedly decreased AG levels, and the M-index, a measure of insulin sensitivity, was significantly improved in the six subjects in whom we were able to attain steady-state euglycemia. DAG administration was not accompanied by many side effects when compared with placebo.ConclusionsDAG administration improves glycemic control in obese subjects with type 2 diabetes through the suppression of AG levels. DAG is a good candidate for the development of compounds in the treatment of metabolic disorders or other conditions with a disturbed AG:DAG ratio, such as type 2 diabetes mellitus or Prader–Willi syndrome.

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Developmental Changes in the Pattern of Ghrelin’s Acyl Modification and the Levels of Acyl-Modified Ghrelins in Murine Stomach

Endocrinology ◽

10.1210/en.2004-0645 ◽

2005 ◽

Vol 146 (6) ◽

pp. 2709-2715 ◽

Cited By ~ 40

Author(s):

Yoshihiro Nishi ◽

Hiroshi Hiejima ◽

Hiroharu Mifune ◽

Takahiro Sato ◽

Kenji Kangawa ◽

...

Keyword(s):

Active Form ◽

Peptide Hormone ◽

Decanoic Acid ◽

Biologically Active ◽

Acylated Ghrelin ◽

Amino Acid Peptide ◽

Total Ghrelin ◽

Wet Weight ◽

Milk Lipids ◽

Acyl Ghrelin

Abstract Ghrelin is an acylated peptide hormone secreted primarily from endocrine cells in the stomach. The major active form of ghrelin is a 28-amino acid peptide with an n-octanoyl modification at Ser3 (n-octanoyl ghrelin), which is essential for its activity. In addition to n-octanoyl ghrelin, other forms of ghrelin peptide exist, including des-acyl ghrelin, which lacks an acyl modification, and other minor acylated ghrelin species, such as n-decanoyl ghrelin, whose Ser3 residue is modified by n-decanoic acid. Multiple reports have identified various physiological functions of ghrelin. However, until now, there have been no reports that explore the process of ghrelin acyl modification, and only a few studies have compared the levels of des-acyl, n-octanoyl, and/or other minor populations of acylated ghrelin peptides. In this study we report that the amount of n-octanoyl ghrelin in murine stomachs increases gradually during the suckling period to a maximal level at 3 wk of age and falls sharply after the initiation of weaning. However, the concentration (picomoles per milligram of wet weight tissue) of total ghrelin, which includes des-acyl and all acylated forms of ghrelin peptides with intact C termini in murine stomach, remains unchanged across this suckling-weaning transition. Prematurely weaned mice exhibited a significant decrease in the amount of n-octanoyl or n-decanoyl ghrelin in the stomach. Orally ingested glyceryl trioctanoate, a medium-chain triacylglyceride rich in milk lipids, significantly increased the level of n-octanoyl-modified ghrelin in murine stomach. Fluctuations in the proportion of this biologically active, acyl-modified ghrelin could contribute to or be influenced by the change in energy metabolism during the suckling-weaning transition.

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Ghrelin and acyl ghrelin in preterm infants and maternal blood: relationship with endocrine and anthropometric measures

Acta Endocrinologica ◽

10.1530/eje-07-0410 ◽

2008 ◽

Vol 158 (1) ◽

pp. 27-33 ◽

Cited By ~ 14

Author(s):

Éva Lányi ◽

Ákos Várnagy ◽

Kálmán A Kovács ◽

Tamás Csermely ◽

Mária Szász ◽

...

Keyword(s):

Preterm Infants ◽

Umbilical Vein ◽

Multivariate Regression Analysis ◽

Maternal Blood ◽

Acylated Ghrelin ◽

Anthropometric Measures ◽

Ghrelin Concentration ◽

Anthropometric Features ◽

Total Ghrelin ◽

Acyl Ghrelin

ObjectiveThe objective of the present study was to examine the association of acylated and total ghrelin levels at birth in preterm infants with anthropometric features and with related hormones in infants and their mothers.DesignProspective, descriptive study.MethodsIn total 23 pregnant women and their 26 preterm infants were involved in the study (3 twin pregnancies; gestational age, 25–35 weeks). Maternal and umbilical vein blood samples were taken after the delivery. Serum acylated and total ghrelin, leptin, cortisol, insulin, GH, and glucose were determined.ResultsThe mean level of acylated ghrelin concentration was higher in the maternal than in the cord blood (P<0.01) and there was a significant correlation between the fetal and maternal acylated ghrelin levels (P<0.01). The total ghrelin concentration was higher in neonates than in mothers (P<0.01), but there was no correlation between them. The multivariate regression analysis for fetal acylated and maternal total ghrelin as dependent variables shows that the fetal acylated ghrelin has two independent predictors, the maternal acylated ghrelin (P<0.01) and the fetal cortisol (P<0.05), whereas the maternal total ghrelin has only one independent predictor, the maternal glucose (P<0.05).ConclusionsThese data provide the first evidence that umbilical cord acylated ghrelin concentrations are lower than in maternal blood and support the hypothesis that the acylation process in the fetus is partly affected by cortisol and the placenta may play a role in this process.

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Acylated ghrelin and des-acyl ghrelin exert different effects on the gastrointestinal motility in conscious rats

International Congress Series ◽

10.1016/j.ics.2005.11.115 ◽

2006 ◽

Vol 1287 ◽

pp. 361-367

Author(s):

Mineko Fujimiya ◽

Akihiro Asakawa ◽

Kazunori Fujino ◽

Chih-Yen Chen ◽

Akio Inui

Keyword(s):

Gastrointestinal Motility ◽

Acylated Ghrelin ◽

Conscious Rats ◽

Acyl Ghrelin

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Effects of glucose and insulin on acyl ghrelin and desacyl ghrelin, leptin, and adiponectin in pregnant women with diabetes

Metabolism ◽

10.1016/j.metabol.2009.09.033 ◽

2010 ◽

Vol 59 (6) ◽

pp. 841-847 ◽

Cited By ~ 11

Author(s):

William Gibson ◽

Jianhua Liu ◽

Bruce Gaylinn ◽

Michael O. Thorner ◽

Graydon S. Meneilly ◽

...

Keyword(s):

Pregnant Women ◽

Desacyl Ghrelin ◽

Acyl Ghrelin

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Acylated ghrelin concentrations are markedly decreased during pregnancy in mothers with and without gestational diabetes: relationship with cholinesterase

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90866.2008 ◽

2009 ◽

Vol 296 (5) ◽

pp. E1093-E1100 ◽

Cited By ~ 27

Author(s):

Elaine Tham ◽

Jianhua Liu ◽

Sheila Innis ◽

David Thompson ◽

Bruce D. Gaylinn ◽

...

Keyword(s):

Growth Hormone ◽

Gestational Diabetes ◽

Test Meal ◽

Postpartum Period ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Area Under The Curve ◽

Inhibitory Effect ◽

Acylated Ghrelin ◽

Desacyl Ghrelin

Acylated (octanoylated) ghrelin stimulates food intake and growth hormone secretion and is deacylated into desacyl ghrelin by butyrylcholinesterase. Acylated and desacyl ghrelin both promote adipogenesis. Ghrelin concentrations decrease with hyperglycemia and hyperinsulinism. We hypothesized that 1) acylated ghrelin increases during pregnancy, contributing positively to energy balance, but is lower in women with gestational diabetes and 2) butyrylcholinesterase activity is inversely correlated with acylated ghrelin concentrations. In a first group of subjects, using two-site sandwich ghrelin assays that specifically detect full-length forms, we investigated women with and without gestational diabetes ( n = 14/group) during pregnancy and after delivery. We examined whether changes in ghrelin during a test meal were correlated with changes in pituitary growth hormone [assessed through calculation of the area under the curve (AUC) during the test meal]. In postpartum subjects, the percent of total ghrelin that is acylated was four to five times higher than previously observed using single antibody assays. During pregnancy, acylated ghrelin concentrations (mean ± SE) were lower compared with the postpartum period throughout the meal (AUC 1.2 ± 0.2 vs. 10.2 ± 1.9 ng·ml−1·90 min−1, P < 0.001). In the postpartum, acylated ghrelin and growth hormone were positively correlated ( r = 0.50, P = 0.007). Desacyl (but not acylated) ghrelin was increased in subjects with gestational diabetes during and after pregnancy (AUC 15.4 ± 1.9 vs. 8.6 ± 1.2 ng·ml−1·90 min−1, P = 0.005). In a second group of subjects ( n = 13), acylated ghrelin was similarly suppressed during pregnancy. Circulating octanoate concentrations (3.1 ± 0.5 vs. 4.5 ± 0.6 μg/ml, P = 0.029) and cholinesterase activity (705 ± 33 vs. 1,013 ± 56 U/ml, P < 0.001) were lower during pregnancy compared with the postpartum period. In conclusion, acylated ghrelin markedly decreases during pregnancy, likely because of a decrease in the acylation process. Desacyl ghrelin increases in gestational diabetes, possibly reflecting resistance to the inhibitory effect of insulin on ghrelin secretion.

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Does des-acyl ghrelin improve glycemic control by decreasing acylated ghrelin levels?

Acta Endocrinologica ◽

10.1530/eje-14-1131 ◽

2015 ◽

Vol 173 (1) ◽

pp. L1-L2 ◽

Cited By ~ 1

Author(s):

Bruce D Gaylinn ◽

Leon S Farhy ◽

Ralf Nass ◽

Jenny Tong ◽

Michael O Thorner

Keyword(s):

Glycemic Control ◽

Acylated Ghrelin ◽

Acyl Ghrelin

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A Systematic Review and Meta-Analysis Finds Increased Blood Levels of All Forms of Ghrelin in Both Restricting and Binge-Eating/Purging Subtypes of Anorexia Nervosa

Nutrients ◽

10.3390/nu13020709 ◽

2021 ◽

Vol 13 (2) ◽

pp. 709

Author(s):

Maria Seidel ◽

Signe Markmann Jensen ◽

Darren Healy ◽

Aakriti Dureja ◽

Hunna J. Watson ◽

...

Keyword(s):

Anorexia Nervosa ◽

Treatment Success ◽

Acute Stage ◽

Blood Levels ◽

Healthy Controls ◽

Cross Sectional ◽

Desacyl Ghrelin ◽

Total Ghrelin ◽

Acyl Ghrelin

Anorexia nervosa (AN) is a severe psychiatric condition associated with high mortality and chronicity. The hunt for state, trait, subtyping, and prognostic biomarkers is ongoing and the orexigenic hormone ghrelin and its different forms, acyl ghrelin and desacyl ghrelin, have been proposed to be increased in AN, especially in the restrictive subtype. A systematic literature search was performed using established databases up to 30 November 2020. Forty-nine studies met inclusion criteria for cross-sectional and longitudinal meta-analyses on total ghrelin, acyl ghrelin, and desacyl ghrelin. All forms of ghrelin were increased in the acute stage of anorexia nervosa during fasting compared to healthy controls. Previous notions on differences in ghrelin levels between AN subtypes were not supported by current data. In addition, a significant decrease in total ghrelin was observed pre-treatment to follow-up. However, total ghrelin levels at follow-up were still marginally elevated compared to healthy controls, whereas for acyl ghrelin, no overall effect of treatment was observed. Due to heterogeneity in follow-up designs and only few data on long-term recovered patients, longitudinal results should be interpreted with caution. While the first steps towards a biomarker in acute AN have been completed, the value of ghrelin as a potential indicator of treatment success or recovery status or its use in subtype differentiation are yet to be established.

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