Biomedical subjects

Philippe Zizzari

Publications and source records attributed to Philippe Zizzari.

6 recordsLinked to original sources

PubMed2005

Delayed age-associated decrease in growth hormone pulsatile secretion and increased orexigenic peptide expression in the Lou C/JaLL rat.

Since modifications in the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis and/or caloric restriction are involved in the ageing process, GH secretory profiles, total IGF-1, ghrelin, and leptin plasma levels and expression of genes implicated in somatotrope axis and food intake regulation in hypothalamus and pituitary were compared in 3-, 12-, and 24-month-old male Lou C/Jall rats and their parent strain, the Wistar rats. The Lou C/Jall strain may appear as a healthy ageing model, since it does not become obese with age and maintains its caloric intake at 2 years of age. The GH pulsatile secretion decreased from 3 months in Wistar, but only after 12 months in Lou C/Jall rats. The IGF-1 levels were lower in Lou C/Jall rats and decreased more steeply with ageing as compared with Wistar rats. The total ghrelin levels were higher in young Lou C/Jall rats than in Wistar rats, but increased similarly with age in both strains. The leptin concentrations increased with ageing only in Wistar rats. By semiquantitative reverse-transcription polymerase chain reaction, pituitary GH secretagogue receptors and GH mRNA levels were more abundant in Lou C/Jall rats, and the latter decreased with ageing in Wistar rats only. Hypothalamic growth-hormone-releasing hormone and GH secretagogue receptor mRNA levels were similar in both strains and transiently increased only in middle-aged Wistar rats. Agouti-related peptide, neuropeptide Y, and orexin mRNA levels were more abundant in the Lou C/Jall rat hypothalamus, and the two former tended to further increase with age only in this strain. Conversely, the hypothalamic pro-opiomelanocortin mRNA levels were higher in old Wistar rats. In conclusion, ageing in Lou C/Jall rats is associated with a delayed decrease in pulsatile GH secretion in the presence of a lower IGF-1 tone and an increase in the expression of orexigenic neuropeptides in the hypothalamus.

Aging↗

PubMed2004

The role of the small bowel in the regulation of circulating ghrelin levels and food intake in the obese Zucker rat.

Circulating levels of ghrelin, a stomach peptide that promotes food intake, rise before and fall after meal. We aimed to investigate whether there is an independent contribution of the small bowel to the regulation of ghrelin and appetite. A duodenal-jejunal bypass (DJB) with preservation of normal gastric volume and exposure to nutrients was performed in 12-wk-old obese Zucker ZDF fa/fa rat. Food intake, weight gain, 48-h fasting, and 24-h refeeding levels of total and acylated ghrelin were measured. The DJB was challenged against gastric banding (GB), diet, and a sham operation in matched animals. Normal controls were age-matched Wistar rats, which underwent either DJB or a sham operation. The Zucker obese animals showed a paradoxical increase of acylated ghrelin levels after refeeding (+30% with respect to fasting levels; P = 0.001), an abnormality that was completely reversed only by the DJB (-30%; P = 0.01) but not after GB, diet, or sham operation. In obese rats, the DJB resulted in significantly less food intake and weight gain compared with both GB (P < 0.05) and sham operation (P < 0.01). In sharp contrast, the DJB did not alter food intake and weight gain in normal rats. The DJB does not physically restrict the flow of food but restores meal-induced suppression of acylated ghrelin and significantly reduces food intake in Zucker obese rats. These findings suggest an independent intestinal contribution to the regulation of the dynamic ghrelin response to eating and the possibility that defective signaling from the proximal bowel could be involved in the pathogenesis of obesity/hyperphagia.

Anastomosis, Roux-en-Y↗

PubMed2004

Novel analogs of ghrelin: physiological and clinical implications.

Ghrelin, the 28 amino acid peptide recently identified as the natural ligand for the growth hormone (GH) secretagogue (GHS) receptor, has multiple activities in addition to stimulation of GH secretion, including stimulation of feeding and weight gain. To utilize these actions for potential therapeutic benefit, we have produced analogs of human ghrelin with enhanced metabolic stability, affinity for the GHS receptor, and efficacy in stimulating weight gain. We have also discovered an analog of ghrelin, BIM-28163, that is an antagonist at the GHS receptor and that fully inhibits GHS receptor activation induced by native ghrelin. In vivo, BIM-28163 does not increase GH secretion but fully blocks ghrelin-induced GH secretion. In contrast, BIM-28163 acts as a full agonist with regard to the ghrelin actions of stimulating weight gain and food intake. These results suggest that a receptor other than the GHS receptor mediates the actions of ghrelin on feeding and weight gain. This concept is strengthened by our observation that at certain hypothalamic sites, BIM-28163 acts as an antagonist of ghrelin-induced neuronal activation, while at other sites, both ghrelin and BIM-28163 induce neuronal activation via the same receptor. Collectively, these results indicate the existence of a novel ghrelin receptor that may regulate the feeding activity of ghrelin. Using BIM-28163 as a tool to define the endogenous role of ghrelin in normal GH secretion, we have demonstrated that antagonism of the GHS receptor in normal rats does not impair the pulsatility of GH secretion but lowers the pulse amplitude and mean GH level. These results demonstrate that endogenous ghrelin acts to amplify the basic pattern of GH secretion established by the interplay of hypothalamic GH-releasing hormone and somatostatin. These studies demonstrate the feasibility of creating ghrelin analogs that are selective for specific activities, as well as their utility in dissecting the role of ghrelin in both normal physiology and specific pathologies.

Animals↗

PubMed2003

Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women.

Ghrelin, a 28-amino acid octanoylated peptide, has recently been identified in rat stomach as an endogenous ligand for the GH secretagogue receptor. In addition to GH-releasing properties, exogenous ghrelin injections exert orexigenic effects in both rodents and humans. As the endogenous peptide appears directly related to feeding behavior, we assessed its plasma levels in anorexia nervosa (AN) patients before and after renutrition and in constitutionally thin subjects with body mass indexes (BMIs) equivalent to those of AN women but with no abnormal feeding behavior. The relationships between plasma ghrelin levels and other neuroendocrine and nutritional parameters, such as GH, leptin, T3, and cortisol, were also investigated. In AN patients, morning fasting plasma ghrelin levels were doubled compared with levels in controls, constitutionally thin subjects, and AN patients after renutrition. Twenty-four-hour plasma ghrelin, GH, and cortisol levels determined every 4 h were significantly increased, whereas 24-h plasma leptin levels were decreased in AN patients compared with controls and constitutionally thin subjects. Both plasma ghrelin and leptin levels returned to control values in AN patients after renutrition. Constitutionally thin subjects displayed intermediate 24-h plasma ghrelin and leptin levels, significantly different from controls and AN patients, whereas GH and cortisol were not modified. Ghrelin was negatively correlated with BMI, leptin, and T(3) in controls, constitutionally thin subjects, and AN patients, whereas no correlation was found between GH and ghrelin or between cortisol and ghrelin. Ghrelin and BMI or T3 were still correlated after renutrition, suggesting that ghrelin is also a good nutritional indicator. Basal and GHRH-stimulated GH release were significantly increased in AN patients only. In conclusion, ghrelin is increased in AN and constitutionally thin subjects who display very low BMI but different eating behaviors, suggesting that not only is ghrelin dependent on body fat mass, but it is also influenced by nutritional status. Even though endogenous ghrelin is not strictly correlated with basal GH secretion, it may be involved in the magnitude of GHRH-induced GH release in AN patients.

Adolescent↗

PubMed2002

Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats.

Ghrelin, an endogenous ligand for the GHS receptor, stimulates GH secretion and gastrointestinal motility and has orexigenic effects. In this study, the relationships between ghrelin, GH secretion, feeding behavior, and sleep-wake patterns were investigated in adult male rats. The half-life of exogenous ghrelin (10 microg i.v.) in plasma was about 30 min. Repeated administration of ghrelin at 3- to 4-h intervals (one during lights-on and two during lights-off periods) increased GH release and feeding activity, and decreased rapid eye movement sleep duration. Endogenous plasma ghrelin levels exhibited pulsatile variations that were smaller and less regular compared with those of GH. No significant correlation between GH and ghrelin circulating levels was found, although mean interpeak intervals and pulse frequencies were close for the two hormones. In contrast, ghrelin pulse variations were correlated with food intake episodes in the lights off period, and plasma ghrelin concentrations decreased by 26% in the 20 min following the end of the food intake periods. A positive correlation between ghrelin levels and active wake was found during the first 3 h of the dark period only. In conclusion, ghrelin, in addition to affecting GH secretion, gastrointestinal motility, and feeding activity, also modifies sleep-wake patterns. However, a direct action of ghrelin per se or the indirect effects of feeding (and all of its attendant metabolic sequelae) on sleep cannot be differentiated. Moreover, ghrelin secretion is pulsatile and directly related to feeding behavior only.

Activity Cycles↗

PubMedDate not supplied

[Ghrelin: a striking example of neuroendocrine peptide pleiotropy].

Ghrelin, a peptide predominantly produced by the stomach, has been discovered as a natural ligand of the growth hormone secretagogue receptor (GHS-R) type 1a. Shortly there after, it attracted enormous interest since it appeared as the first peripheral orexigenic factor. Besides, ghrelin exerts other neuroendocrine metabolic and non-endocrine actions (e.g. cardiovascular activities) that may rely on the widespread distribution of ghrelin and its receptor (GHS-R). The existence of several GHS-R subtypes and evidences that neuroendocrine and metabolic but not all other ghrelin actions are dependent on acylation on serine 3 add further complexity to the system whose major physiological role remains to be definitely elucidated. Ghrelin knockout(-/-) mice are neither anorectic nor dwarf though GHS-R-/- are slightly underweight and do not respond to ghrelin with increased GH secretion or appetite. Thus, the continuation of the fascinating ghrelin story as well as its potential pathophysiological implications in endocrinology and internal medicine remain open avenues for future investigations.

Animals↗