In vitro metabolic stability of obestatin: Kinetics and identification of cleavage products

Vergote, Valentijn; Dorpe, Sylvia Van; Peremans, Kathelijne; Burvenich, Christian; Spiegeleer, Bart De

doi:10.1016/j.peptides.2008.05.018

Cited by 52 publications

(46 citation statements)

References 29 publications

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“…2 reflexes the relative importance of the different peptides found, resulting from the cleavage of the indicated peptide bond compared to the total quantity of degradants. For non-iodinated mouse obestatin incubated in mouse plasma, liver and kidney (data not shown), the obtained proteolytic fragments were consistent with a previous study [29].…”

Section: Resultssupporting

confidence: 91%

“…In attempts to explain the conflicting results on obestatin, several functional quality issues have been investigated in detail: presence of synthesis impurities in commercially available peptides [6] and formation of mixtures during radio-iodination [27,28]. As for most endogenous-derived peptide leads, obestatin has only little resistance to systemic plasma and tissue proteases [29] which may result in a failure to demonstrate convincing in vivo effects [30]. Currently, some recent studies investigated fragments or modified obestatin derivatives to provide protection against enzymatic degradation.…”

Section: Introductionmentioning

confidence: 99%

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C-type natriuretic peptide: A new cardiac mediator

2013

Peptides

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a b s t r a c tDifferent iodinated mouse obestatin peptides have been characterized toward their in vitro stability in the main metabolic compartments plasma, liver and kidney. Using HPLC-UV for quantification, significant differences in the degradation kinetics of the iodinated peptides, arising from both enzymatic proteolysis and dehalogenation, were found when compared to the native, unmodified peptide. HPLC-MS/MS analysis demonstrated that the cleavage sites were dependent upon the biological matrix and the location of the amino acid residue incorporating the iodine atom(s). The degrading proteases were found to target peptide bonds further away from the iodine incorporation, while proteolytic cleavages of nearby peptide bonds were more limited. Diiodinated amino acid residue containing peptides were found to be more susceptible to deiodination than the mono-iodinated derivative. In plasma, the percentage of peptide degradation solely attributed to deiodinase activity after 20 min incubation reached up to 25% for 2,5-diiodo-H 19 -obestatin compared to 20% and only 3% for (3,5-diiodo-Y 16 )-and (3-iodo-Y 16 ) obestatin, respectively. Hence, our results demonstrate that the different iodinated peptides pose significantly different metabolization properties and thus, also different biological activities are expected for peptides upon iodination.

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Section: Resultssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

C-type natriuretic peptide: A new cardiac mediator

2013

Peptides

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“…However, another recent study failed to show an inhibitory effect of intracerebroventricular obestatin on water intake in mice (Annemie et al, 2009). Three recent studies also remind us to take major instability and impurity of obestatin peptides under biomedical investigations into account during interpretation for those discrepant data obtained in feeding behavior (Pan et al, 2006;De Spiegeleer et al, 2008;Vergote et al, 2008). Hence, in-depth exploration of obestatin on mammalian appetitive behavior, including microstructures of feeding and correction of situational physiological bias, should be further conducted ).…”

Section: Normal Physiology Of Obestatin and Regulation Of Its Expmentioning

confidence: 99%

“…However, another study claimed that intraperitoneal administration of obestatin did not elicit c-fos immunoreactivity in ingestive behavior-relevant brain nuclei in rodents . The rapid intracellular degradation and major instability of obestatin in the plasma should be taken into account during data interpretation (Pan et al, 2006;Vergote et al, 2008).…”

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confidence: 99%

Ghrelin Gene Products and the Regulation of Food Intake and Gut Motility

et al. 2009

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“…The real translational relevance of our current findings, however, still remains to be determined. Among the issues to be addressed, for example, is that obestatin has a short half-life and is rapidly degraded by several proteases located in blood and tissues (34). Development of more stable obestatin analogs resistant to endogenous degradation and providing improved bioactivity, as well as further understanding about its native receptor(s) and the related downstream signaling pathways, may certainly help to fully assess the therapeutic capabilities of this peptide.…”

Section: Discussionmentioning

confidence: 99%

Vascular Effects of Obestatin in Lean and Obese Subjects

Schinzari

Veneziani

et al. 2017

Diabetes

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Obese patients have impaired vasodilator reactivity and increased endothelin 1 (ET-1)-mediated vasoconstriction, two abnormalities contributing to vascular dysfunction. Obestatin, a product of the ghrelin gene, in addition to favorable effects on glucose and lipid metabolism, has shown nitric oxide (NO)-dependent vasodilator properties in experimental models. Given these premises, we compared the effects of exogenous obestatin on forearm flow in lean and obese subjects and assessed its influence on ET-1-dependent vasoconstrictor tone in obesity. In both lean and obese participants, infusion of escalating doses of obestatin resulted in a progressive increase in blood flow from baseline (both P < 0.001). This vasodilation was predominantly mediated by enhanced NO activity, because N G -monomethyl-L-arginine markedly blunted the flow response to obestatin in both groups (both P < 0.05 vs. saline). In obese subjects, antagonism of ET A receptors by BQ-123 increased forearm flow during saline (P < 0.001) but did not induce additional vasodilation (P > 0.05) during obestatin. Circulating obestatin levels were not different between lean and obese participants (P = 0.41). Our findings indicate that obestatin causes NO-dependent vasodilation in the human circulation. This effect is preserved in obesity, where it is accompanied by reduced ET-1-mediated vasoconstriction. These latter observations make obestatin a promising target for vascular prevention in obesity and diabetes.According to the current figures of the World Health Organization, the worldwide prevalence of obesity is still on the rise, carrying an increased burden of type 2 diabetes and other untoward consequences, especially cardiovascular complications. Impaired vasodilator reactivity has been recognized as an early hemodynamic abnormality characteristic of these patients (1), but also increased vasoconstrictor tone, predominantly resulting from enhanced endothelin (ET)-1 activity (2,3), has been shown to importantly contribute to their vascular dysfunction and damage.Obestatin was identified in 2005 as a ghrelin-associated peptide derived from alternative splicing of the common precursor prepro-ghrelin and was originally reported to reduce food intake and gastric emptying through activation of the G-protein-coupled receptor (GPCR) GPR39 (4). Even though these effects on feeding behavior and gastrointestinal motion have been subsequently disputed and the precise identity of its cognate receptor(s) is still a matter of debate (5), obestatin indisputably exerts a variety of effects in different cell types, including pancreatic b-cells, where it increases survival and proliferation by inhibiting apoptosis and inflammation (6,7). In line with these actions, other favorable effects of obestatin have been observed on glucose and lipid metabolism, such as increased glucose uptake and insulin sensitivity as well as inhibition of lipolysis in human adipocytes (7,8).Interestingly, in addition to its helpful metabolic properties, obestatin has been shown to provide va...

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In vitro metabolic stability of obestatin: Kinetics and identification of cleavage products

Cited by 52 publications

References 29 publications

C-type natriuretic peptide: A new cardiac mediator

C-type natriuretic peptide: A new cardiac mediator

Ghrelin Gene Products and the Regulation of Food Intake and Gut Motility

Vascular Effects of Obestatin in Lean and Obese Subjects

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