Unacylated Ghrelin Rapidly Modulates Lipogenic and Insulin Signaling Pathway Gene Expression in Metabolically Active Tissues of GHSR Deleted Mice

Delhanty, Patric J. D.; Sun, Yuxiang; Visser, Jenny A.; Kerkwijk, Anke van; Huisman, Martin; IJcken, Wilfred F. J. van; Swagemakers, Sigrid; Smith, Roy G.; Themmen, Axel P. N.; Lely, Aart-Jan van der

doi:10.1371/journal.pone.0011749

Cited by 110 publications

(87 citation statements)

References 57 publications

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“…This is in line with other observations on its insulin-sensitizing effects in rodents (35) and humans (3,5). Although we observed significant improvements in the M-index during DAG infusion in the HEC study, it is difficult to draw strong conclusions since this was assessed in only six subjects.…”

Section: European Journal Of Endocrinologysupporting

confidence: 86%

“…No specific receptor for DAG has been identified to date, but there is indirect evidence for its existence. For example, we found that DAG treatment of Ghsr1a knockout mice rapidly affected the expression of genes involved in glycemic control and lipid metabolism, indicating a mechanism of action independent of GHS-R1a (35).…”

Section: European Journal Of Endocrinologymentioning

confidence: 93%

“…However, direct metabolic effects of DAG cannot be excluded in view of the reported GHS-R1a-independent (AG-independent) effects of DAG, which include improved glycemic control through the modulation of glucose and medium-chain fatty acid uptake (2,6,35,36). Another indication of the importance of DAG levels as a potential physiological inhibitor of AG action has been reported already by the above-mentioned studies of transgenic mice overexpressing DAG (32,33,37), which were lighter and shorter compared with controls.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

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

Özcan¹,

Neggers²,

Miller³

et al. 2014

European Journal of Endocrinology

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Objective: The 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 methods: A double-blind, placebo-controlled cross-over study design was implemented, using overnight continuous infusions of 3 and 10 mg DAG/kg per h and placebo to study the effects on a SBM. During a HEC, we studied the insulin sensitivity. Results: We 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. Conclusions: DAG 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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Section: European Journal Of Endocrinologysupporting

confidence: 86%

Section: European Journal Of Endocrinologymentioning

confidence: 93%

Section: European Journal Of Endocrinologymentioning

confidence: 99%

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

Özcan¹,

Neggers²,

Miller³

et al. 2014

European Journal of Endocrinology

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“…(3, 9, 17) Indeed, des-acyl ghrelin has been shown to modulate the expression of metabolic genes in GRLN-deleted mice tissues, to inhibit lipolysis in adipocytes, and to counteract the ghrelin diabetogenic actions in animals and humans. (18)(19)(20) On the basis of des-acyl ghrelin inabilit to bind GRLN, the existence of a different and yet unknown receptor involved in the effects of the peptide has been proposed. Indeed, common binding sites for both ghrelin and des-acyl ghrelin have been shown in pancreatic β-cells and in a variety of cell types, where both ghrelin and des-acyl ghrelin exert similar effects.…”

Section: Introductionmentioning

confidence: 99%

Des-Acyl Ghrelin Fragments and Analogues Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets and Prevent Diabetes in Streptozotocin-Treated Rats

Granata

Settanni

Julien³

et al. 2012

J. Med. Chem.

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Des-acyl ghrelin, although devoid of binding to ghrelin receptor (GRLN), exerts many biological effects, including regulation of glucose and lipid metabolism. Indeed, des-acyl ghrelin promotes pancreatic β-cell and human islet cell survival and prevents diabetes in streptozotocin (STZ) treated rats. We investigated whether des-acyl ghrelin fragments excluding serine 3 , which is essential for binding to GRLN, would display similar actions. Among the different compounds tested, des-acyl ghrelin (6)(7)(8)(9)(10)(11)(12)(13) and des-acyl ghrelin (6)(7)(8)(9)(10)(11)(12)(13) with alanine substitutions or cyclization, but not with d-amino acid substitutions, showed the best survival effect, similar to des-acyl ghrelin. Des-acyl ghrelin (6)(7)(8)(9)(10)(11)(12)(13) even prevented diabetes in STZ-treated rats and protected human circulating angiogenic cells from oxidative stress and senescence, similar to des-acyl ghrelin. These results suggest that not only fulllength des-acyl ghrelin but also short des-acyl ghrelin fragments have clear beneficial effects on several tissues in vitro and in vivo. Ghrelin is a 28 amino acid peptide mainly produced by the stomach but also in other tissues such as the gastrointestinal tract and the pancreas.(1, 2) Ghrelin potently stimulates growth hormone (GH) release from the pituitary and exerts orexigenic activities at the central level. (3) These neuroendocrine actions require acylation on the third serine residue by ghrelin O-acyl transferase (GOAT), and ghrelin acylaton is essential for binding to its receptor, the GH secretagogue receptor type 1a (GHS-R1a), lately designated GRLN.(1, 4-8) Besides the hypothalamus-pituitary and other central areas, GRLN is distributed in peripheral tissues, including the endocrine pancreas and adipose tissue.(2, 3) Consistently, ghrelin elicits many peripheral actions, including regulation of pancreatic β-cell function and influence on glucose and lipid metabolism.(9-12) Mice deleted for both ghrelin and GRLN genes show improved glucose tolerance and insulin secretion and sensitivity under high-fat diet treatment. In obese, leptindeficient (ob/ob) mice, ablation of ghrelin was found to increase insulin release and to reduce hyperglycemia, suggesting negative effects of ghrelin on insulin secretion and glucose metabolism.(13, 14) Notably, ghrelin infusion in humans induces acute insulin resistance and lipolysis, and ghrelin levels are strongly increased in insulin-resistant obese individuals, suggesting that ghrelin may contribute to insulin resistance in obesity.(15, 16) At variance with ghrelin, des-acyl ghrelin is devoid of endocrine activities and GRLN binding. However, des-acyl ghrelin is the most abundant circulating form of ghrelin, exerting a variety of effects, including positive actions on glucose and lipid metabolism.(3, 9, 17) Indeed, des-acyl ghrelin has been shown to modulate the expression of metabolic genes in GRLN-deleted mice tissues, to inhibit lipolysis in adipocytes, and to counteract the ghrelin diabetogenic actions in ...

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“…Still, DAG can change gene expression in liver tissue, as DAG rapidly modulates lipogenic and insulin signaling pathway gene expression in metabolically active tissues of GHSR deleted mice [11].…”

mentioning

confidence: 99%

Ghrelin: a new treatment for non-alcoholic fatty liver disease?

Delhanty

Lely

2012

Endocrine

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Unacylated Ghrelin Rapidly Modulates Lipogenic and Insulin Signaling Pathway Gene Expression in Metabolically Active Tissues of GHSR Deleted Mice

Cited by 110 publications

References 57 publications

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

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

Des-Acyl Ghrelin Fragments and Analogues Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets and Prevent Diabetes in Streptozotocin-Treated Rats

Ghrelin: a new treatment for non-alcoholic fatty liver disease?

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