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Obestatin partially affects ghrelin stimulation of food intake and growth hormone secretion in rodents

Unité Mixte de Recherche, 549 Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine, Université Paris-Descartes, Paris, France.
Endocrinology (Impact Factor: 4.64). 05/2007; 148(4):1648-53. DOI: 10.1210/en.2006-1231
Source: PubMed

ABSTRACT Administration of ghrelin, an endogenous ligand for the GH secretagogue receptor 1a (GHSR 1a), induces potent stimulating effects on GH secretion and food intake. However, more than 7 yr after its discovery, the role of endogenous ghrelin remains elusive. Recently, a second peptide, obestatin, also generated from proteolytic cleavage of preproghrelin has been identified. This peptide inhibits food intake and gastrointestinal motility but does not modify in vitro GH release from pituitary cells. In this study, we have reinvestigated obestatin functions by measuring plasma ghrelin and obestatin levels in a period of spontaneous feeding in ad libitum-fed and 24-h fasted mice. Whereas fasting resulted in elevated ghrelin levels, obestatin levels were significantly reduced. Exogenous obestatin per se did not modify food intake in fasted and fed mice. However, it inhibited ghrelin orexigenic effect that were evident in fed mice only. The effects of obestatin on GH secretion were monitored in superfused pituitary explants and in freely moving rats. Obestatin was only effective in vivo to inhibit ghrelin stimulation of GH levels. Finally, the relationship between octanoylated ghrelin, obestatin, and GH secretions was evaluated by iterative blood sampling every 20 min during 6 h in freely moving adult male rats. The half-life of exogenous obestatin (10 microg iv) in plasma was about 22 min. Plasma obestatin levels exhibited an ultradian pulsatility with a frequency slightly lower than octanoylated ghrelin and GH. Ghrelin and obestatin levels were not strictly correlated. In conclusion, these results show that obestatin, like ghrelin, is secreted in a pulsatile manner and that in some conditions; obestatin can modulate exogenous ghrelin action. It remains to be determined whether obestatin modulates endogenous ghrelin actions.

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Available from: Jacques Epelbaum, Jul 31, 2015
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    • "Its participation in the regulation of energetic homeostasis in humans has been suggested, and initial data pointed towards the idea that obestatin was driving an anorexigenic message in contraposition to the orexigenic effect of ghrelin. However, various recent studies have shown conflictive results regarding this (Nakahara et al. 2008; Nogueiras et al. 2007; Zhang et al. 2005; Zizzari et al. 2007). In a recent study, we found that obestatin was not associated to weight loss or diminished appetite or decreased eating behaviour frequently observed in the ageing phenomenon and referred to as anorexia of aged people (Mora et al. 2012a). "
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    ABSTRACT: Obestatin has been proposed to have anorexigenic and anti-ghrelin actions. The objective was to study obestatin concentrations in relation to handgrip strength, functional capacity and cognitive state in old women. The prospective study included 110 women (age, 76.93 ± 6.32) from the Mataró Ageing Study. Individuals were characterized by anthropometric variables, grip strength, Barthel and assessment of cognitive impairment [Mini Cognoscitive Examination (MCE) Spanish version], depressive status by the Geriatric Depression Scale (GDS) and frailty by the Fried criteria. Obestatin was measured by IRMA. Obestatin showed negative correlation to handgrip at basal time point (r = −0.220, p = 0.023) and at 2-year follow-up (r = −0.344, p = 0.002). Obestatin, divided into quartiles, showed a negative lineal association with handgrip: 11.03 ± 4.88 kg in first, 8.75 ± 4.08 kg in second, 8.11 ± 3.66 kg in third and 7.61 ± 4.08 kg in fourth quartile (p = 0.018). Higher obestatin levels were associated to increased weakness (categorized by handgrip of frailty criteria): 2.24 ± 0.42 ng/ml in weak vs. 1.87 ± 0.57 ng/ml in non-weak (p = 0.01). The decrease of either MCE or Barthel scores at 2-year follow-up was significantly higher in individuals in the fourth quartile of obestatin in comparison with individuals in the first quartile (p = 0.046 and p = 0.019, respectively). No association was found between obestatin and GDS score and neither with frailty as a condition. Obestatin is associated to low muscle strength, and impaired functional and cognitive capacity in old women participating in the Mataró Ageing Study.
    Journal of the American Aging Association 12/2013; 35(6). DOI:10.1007/s11357-013-9532-0 · 3.45 Impact Factor
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    • "Obestatin by itself did not induce any change in GHRH neurons but it mainly blocked the ghrelin-induced decrease of GABA inputs and ghrelin-induced membrane depolarization and increase of action potential firing rate, thereby reversing excitatory ghrelin effects on both hypothalamic GHRH release and GHRH neuron excitability. Such observations may explain in part the observed lack of effect of obestatin on GH secretion when it is not injected concomitantly with ghrelin (Bresciani et al., 2006; Yamamoto et al., 2007) and are in keeping with the observation that obestatin is only effective in vivo, but not in superfused pituitaries ex vivo, to inhibit ghrelin stimulation of GH levels (Zizzari et al., 2007). The absence of effect of obestatin on ghrelin-induced internalization of GHS-R1a also shows that obestatin does not activate the GHS-R. "
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    ABSTRACT: Ghrelin, a natural ligand of the growth hormone secretagogue receptor (GHS-R), is synthesized in the stomach but may also be expressed in lesser quantity in the hypothalamus where the GHS-R is located on growth hormone-releasing hormone (GHRH) neurons. Obestatin, a peptide derived from the same precursor as ghrelin, is able to antagonize the ghrelin-induced increase of growth hormone (GH) secretion in vivo but not from pituitary explants in vitro. Thus, the blockade of ghrelin-induced GH release by obestatin could be mediated at the hypothalamic level by the neuronal network that controls pituitary GH secretion. Ghrelin increased GHRH and decreased somatostatin (somatotropin-releasing inhibitory factor) release from hypothalamic explants, whereas obestatin only reduced the ghrelin-induced increase of GHRH release, thus indicating that the effect of ghrelin and obestatin is targeted to GHRH neurons. Patch-clamp recordings on mouse GHRH-enhanced green fluorescent protein neurons indicated that ghrelin and obestatin had no significant effects on glutamatergic synaptic transmission. Ghrelin decreased GABAergic synaptic transmission in 44% of the recorded neurons, an effect blocked in the presence of the GHS-R antagonist BIM28163, and stimulated the firing rate of 78% of GHRH neurons. Obestatin blocked the effects of ghrelin by acting on a receptor different from the GHS-R. These data suggest that: (i) ghrelin increases GHRH neuron excitability by increasing their action potential firing rate and decreasing the strength of GABA inhibitory inputs, thereby leading to an enhanced GHRH release; and (ii) obestatin counteracts ghrelin actions. Such interactions on GHRH neurons probably participate in the control of GH secretion.
    European Journal of Neuroscience 07/2011; 34(5):732-44. DOI:10.1111/j.1460-9568.2011.07787.x · 3.67 Impact Factor
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    • "As obestatin is a gut hormone (produced in the stomach), obestatin may act as an endocrine hormone and may circulate in the blood to reach the brain through the blood brain barrier, it could signal to the brain by affecting primary afferent neurons, or both. Unexpectedly, obestatin rapidly degrades in the plasma and, unlike ghrelin, it is not able to cross the bloodbrain barrier by a saturable transport system (Pan et al., 2006; Vergote et al., 2008; Zizzari et al., 2007). Since the obestatin receptor has not been identified, it is currently difficult to dissect how peripheral obestatin may control central systems, such as feeding. "
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    ABSTRACT: Obestatin is a 23 amino acid, ghrelin gene-derived peptide hormone produced in the stomach and a range of other tissues throughout the body. While it was initially reported that obestatin opposed the actions of ghrelin with regards to appetite and food intake, it is now clear that obestatin is not an endogenous ghrelin antagonist, but it is a multi-functional peptide hormone in its own right. In this review we will discuss the controversies associated with the discovery of obestatin and explore emerging central and peripheral roles of obestatin, which includes adipogenesis, pancreatic homeostasis and cancer.
    Molecular and Cellular Endocrinology 03/2011; 340(1):111-7. DOI:10.1016/j.mce.2011.03.018 · 4.24 Impact Factor
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