Elevated circulating acylated and total ghrelin concentrations along with reduced appetite scores in infants with failure to thrive.

Failure to thrive (FTT) is a term used to describe inadequate growth in infants. The immediate cause is undernutrition. Ghrelin is a potent orexigenic hormone that induces a positive energy balance and enhances appetite. There is no information regarding the possible role of ghrelin in infants with FTT. The aim of this study was 2-fold: 1) to examine circulating ghrelin levels in FTT infants, compared with those of normally growing infants; and 2) to evaluate appetitive behaviors in the two groups. Plasma acylated and total ghrelin concentrations were measured in nine FTT and five normally growing infants (age range, 9-18 mo). Appetite was assessed using three novel appetite measures. Both acylated and total ghrelin levels were significantly elevated in FTT infants compared with controls (p = 0.03 or less). Infants with FTT scored significantly lower than control infants on all appetite measures (p = 0.002 or less). Ghrelin levels were inversely related to appetite, weight velocity, weight/length z-scores, and weight z-score. These findings provide the first evidence that infants with FTT have higher circulating ghrelin concentrations but paradoxically lower appetite scores. Increased ghrelin secretion may reflect an adaptive mechanism attempting to increase appetite and preserve energy balance in response to poor nutritional state.

Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist.

The peptide hormone ghrelin exerts a wide spectrum of activities including the stimulation of GH release, feeding, and gastrointestinal motility, purportedly via the activation of a common receptor, GH secretagogue receptor (since renamed the GRLN-R) The aim of the present study was to determine whether these effects can be separated pharmacologically. Tranzyme Pharma (TZP)-101 is a small-molecule agonist with potent binding affinity (inhibitory constant = 16 nm) and full agonist activity (EC50 = 29 nm, maximum response = 111%) at the human recombinant GRLN-R. Pharmacokinetic profiling of TZP-101 in rat determined a plasma elimination half-life of 99 min and low blood-brain barrier permeability (0.09%). The pharmacological response to TZP-101, administered centrally [intracerebroventricular (icv)] or peripherally (iv), was evaluated in comparison with that of acylated ghrelin. Thus, TZP-101 (iv) accelerated gastric emptying of a liquid meal (2% methylcellulose) similarly to ghrelin (iv). IAlso, TZP-101 (icv) stimulated spontaneous, cumulative food intake in a similar manner to ghrelin (icv). However, unlike ghrelin, TZP-101 did not elicit significant GH release on either central or peripheral administration. Moreover, TZP-101 did not alter ghrelin-induced GH release. n total, these data demonstrate that the GH response can be pharmacologically demarcated from the orexigenic and gastrointestinal responses to ghrelin in rats. The observation that the centrally mediated orexigenic response and the peripherally mediated gastric motility response are pharmacologically associated is consistent with the classification of ghrelin as a brain-gut peptide, whereas the additional action of ghrelin to stimulate GH release (possibly via a distinct signaling pathway) may be considered a complementary mechanism to harmonize somatic growth and body composition with the regulation of energy homeostasis.