Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss

Perreault, Mylène; Istrate, N; Wang, L; Aj, Nichols; Tozzo, Effie; Stricker–Krongrad, Alain

doi:10.1038/sj.ijo.0802640

Cited by 115 publications

(96 citation statements)

References 39 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The ED 50 values when the maximal orexigenic effects were achieved at 250 min (Table 1) were in the range of mg/kg for all of the full-length analogs. The ED 50 value for subcutaneously administered ghrelin in this study was approximately 2 mg/kg, which is similar to that reported previously (Perreault et al, 2004). On the contrary, penta-and octapeptide ghrelin analogs, desoctanoyl ghr, and desoctanoyl [Dpr 3 ]ghr did not show any significant orexigenic effect even at the maximum dose of 10 mg/kg (Table 1).…”

Section: Resultssupporting

confidence: 78%

Characterization of New Stable Ghrelin Analogs with Prolonged Orexigenic Potency

Maletı́nská

Pýchová²,

Holubová³

et al. 2011

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Ghrelin, the only known peripherally produced and centrally acting peptide that stimulates food intake, is synthesized primarily in the stomach and acts through the growth hormone secretagogue receptor (GHS-R1a). In addition to its orexigenic effect, ghrelin stimulates the release of growth hormone (GH). In this study, we investigated the biological properties of fulllength and shortened ghrelin analogs in which octanoylated Ser 3 is replaced with an octanoic acid moiety coupled to diaminopropionic acid (Dpr). Ghrelin analogs stabilized with Dpr(N-octanoyl) in position 3 and noncoded amino acids in position 1 (sarcosine) and/or position 4 (naphthylalanine or cyclohexylalanine) were found to possess affinities similar to those of ghrelin for cell membranes with transfected GHS-R1a. In vivo, the prolonged orexigenic effects of analogs containing Dpr(N-octanoyl) 3 compared with that of ghrelin in adult mice and a similar impact on GH secretion in young mice were found. Full-length [Dpr(N-octanoyl) 3 ]ghrelin and its analogs with a noncoded amino acid in position 1 and/or 4 showed significantly prolonged stability in blood plasma compared with that of ghrelin. Ghrelin analogs with a prolonged orexigenic effect are potential treatments for GH deficiency or cachexia that accompanies chronic diseases. Desoctanoylated ghrelin analogs and N-terminal penta-and octapeptides of ghrelin did not show any biological activity.

show abstract

Section: Resultssupporting

confidence: 78%

Characterization of New Stable Ghrelin Analogs with Prolonged Orexigenic Potency

Maletı́nská

Pýchová²,

Holubová³

et al. 2011

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Despite the rise in total ghrelin output, n-octanoyl ghrelin levels were unaltered in Sst Ϫ/Ϫ mice. Also, fasting resulted in a rise in n-octanoyl ghrelin in both Sst ϩ/ϩ and Sst Ϫ/Ϫ mice without significant changes in total circulating ghrelin levels or stomach ghrelin gene expression, consistent with reports of others showing no effect of fasting on total circulating ghrelin levels in the mouse (29,36). This is in contrast to the effects of fasting in rats, where increases in circulating levels of noctanoyl ghrelin are clearly reflected by increases in total ghrelin levels, where ϳ90% represents the des-acyl form (31).…”

Section: Discussionsupporting

confidence: 77%

Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways

Luque

Gahete²,

Hochgeschwender³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Corticosterone and total ghrelin levels are increased in somatostatin (SST) knockout mice (Sst Ϫ/Ϫ ) compared with SST-intact controls (Sst ϩ/ϩ ). Because exogenous ghrelin can increase glucocorticoids, the question arises whether elevated levels of ghrelin contribute to elevated corticosterone levels in Sst Ϫ/Ϫ mice. We report that Sst Ϫ/Ϫ mice had elevated mRNA levels for pituitary proopiomelanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH), whereas mRNA levels for hypothalamic corticotropin-releasing hormone (CRH) did not differ from Sst ϩ/ϩ mice. Furthermore, SST suppressed pituitary POMC mRNA levels and ACTH release in vitro independently of CRH actions. In contrast, it has been reported that ghrelin increases glucocorticoids via a central effect on CRH secretion and that n-octanoyl ghrelin is the form of ghrelin that activates the GHS-R1a and modulates CRH neuronal activity. Consistent with elevations in total ghrelin levels, Sst Ϫ/Ϫ mice displayed an increase in stomach ghrelin mRNA levels, whereas hypothalamic and pituitary expression of ghrelin was not altered. Despite the increase in total ghrelin levels, circulating levels of n-octanoyl ghrelin were not altered in Sst Ϫ/Ϫ mice. Because glucocorticoids and ghrelin increase in response to fasting, we examined the impact of fasting on the adrenal axis and ghrelin in Sst ϩ/ϩ and Sst Ϫ/Ϫ mice and found that endogenous SST does not significantly contribute to this adaptive response. We conclude that endogenous SST inhibits basal ghrelin gene expression in a tissue specific manner and independently and directly inhibits pituitary ACTH synthesis and release. Thus endogenous SST exerts an inhibitory effect on ghrelin synthesis and on the adrenal axis through independent pathways. somatostatin; adrenocorticotropic hormone; hypothalamic-pituitaryadrenal axis; corticotropin-releasing hormone; pituitary; stomach SOMATOSTATIN (SST), OR ITS SYNTHETIC ANALOGS, can reduce circulating adrenocorticotropic hormone (ACTH) and glucocorticoid levels in rats and humans in vivo (19,43,46). The inhibitory actions of SST are believed to be due, at least in part, to a direct effect on the pituitary. This hypothesis is supported by the fact that SST can block corticotropin-releasing hormone (CRH)-mediated ACTH release in cultures of primary rat pituitary cells, mouse pituitary tumor cells (AtT-20), and cultures of human corticotropinomas (20,25,44), where this effect appears to be mediated by the SST receptors sst2 and/or sst5 (20,43,44). Both the in vivo and in vitro inhibitory effects of SST on ACTH release can be masked by glucocorticoids, where glucocorticoids directly inhibit basal and CRH-mediated ACTH release (19,25). However, a recent study (20) demonstrates that an sst5 selective agonist can inhibit ACTH release in vitro in the presence of glucocorticoids. The inhibitory action of exogenous SST on ACTH release has prompted speculation regarding the role of endogenous SST as a corticotropin release-inhibiting factor (14). More recent observations suppo...

show abstract

“…Another objective of the present study was to examine the effect of GLP2 on food intake in DIO mice, because the release of gut hormones is influenced by the content of the diet, in particular the fat content (Dakin et al 2004), and a different sensitivity to intestinal hormones has been reported between lean and DIO models (Lin et al 2000, Perreault et al 2004. We found that DIO mice were less sensitive to the anorectic action of the peptide than lean animals.…”

Section: Lovshinmentioning

confidence: 82%

Food intake in lean and obese mice after peripheral administration of glucagon-like peptide 2

Baldassano¹,

Bellanca²,

Serio³

et al. 2012

Journal of Endocrinology

View full text Add to dashboard Cite

We investigated the potential anorectic action of peripherally administered glucagon-like peptide 2 (GLP2) in lean and diet-induced obese (DIO) mice. Mice, fasted for 16 h, were injected i.p. with native GLP2 or [Gly 2 ]GLP2, stable analog of GLP2, before or after GLP2 (3-33), a GLP2 receptor (GLP2R) antagonist, or exendin (9-39), a GLP1R antagonist. Food intake was measured at intervals 1, 2, 4, 8, and 24 h postinjection. In addition, we tested in lean mice the influence of [Gly 2 ]GLP2 on gastric emptying and the effects of GLP1 alone or in combination with [Gly 2 ]GLP2 on food intake. [Gly 2 ]GLP2 dose dependently and significantly inhibited food intake in lean and DIO mice. The reduction of food intake occurred in the first hour postinjection and it was sustained until 4 h postinjection in lean mice while it was sustained until 2 h postinjection in DIO mice. GLP2 significantly inhibited food intake in both lean and DIO mice but only in the first hour postinjection. ]GLP2 decreased the gastric emptying rate. Results suggest that GLP2 can reduce food intake in mice in the short term, likely acting at a peripheral level. DIO mice are less sensitive to the anorectic effect of the peptide.

show abstract

Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss

Cited by 115 publications

References 39 publications

Characterization of New Stable Ghrelin Analogs with Prolonged Orexigenic Potency

Characterization of New Stable Ghrelin Analogs with Prolonged Orexigenic Potency

Evidence that endogenous SST inhibits ACTH and ghrelin expression by independent pathways

Food intake in lean and obese mice after peripheral administration of glucagon-like peptide 2

Contact Info

Product

Resources

About