191: Novel insights into the neuroendocrinology of critical illness.
Van den Berghe G. Eur J Endocrinol  2000 Jul;143(1):1-13 

An unexplained hallmark of prolonged critical illness is the fact that food does
not prevent or reverse protein wasting, while fat is paradoxically accrued. This
'wasting syndrome' often persists after the underlying disease has been resolved
and thus perpetuates intensive care dependency. Although the crucial role of an
intact hypothalamus-pituitary axis for homeostasis during stress is well
recognized, the differences between the neuroendocrine changes observed in acute
and prolonged critical illness were only recently described. Novel insights in
this area are reviewed here. The initial endocrine stress response consists
primarily of a peripheral inactivation of anabolic pathways while pituitary
activity is essentially amplified or maintained. These responses presumably
provide the metabolic substrates and host defense required for survival and to
delay anabolism, and thus should be considered as adaptive and beneficial.
Persistence of this acute stress response throughout the course of critical
illness was hitherto assumed. This assumption has now been invalidated, since a
uniformly reduced pulsatile secretion of ACTH, TSH, LH, prolactin (PRL) and GH
has been observed in protracted critical illness, causing diminished stimulation
of several target organs. Impaired pulsatile secretion of anterior pituitary
hormones in the chronic phase of critical illness seems to have a hypothalamic
rather than a pituitary origin, as administration of relevant releasing factors
evoked immediate and pronounced pituitary hormone release. A reduced
availability of TRH, one of the endogenous ligands of the GH-releasing peptide
(GHRP) receptor (such as the recently discovered ghrelin) and, in very long-stay
critically ill men, also of GHRH, appear to be involved. This hypothesis was
further explored by investigating the effects of continuous i.v. infusion of
GHRH, GHRP, TRH and their combinations for several days. Pulsatile secretion of
GH, TSH and PRL was re-amplified by relevant combinations of releasing factors
which also substantially increased circulating levels of IGF-I, GH-dependent
binding proteins, thyroxine and tri-iodothyronine (T3) while avoiding a rise in
reverse T3. Active feedback-inhibition loops prevented overstimulation of target
organs and metabolic improvement was noted with the combined infusion of GHRP
and TRH. Whether this novel endocrine strategy will also enhance clinical
recovery from critical illness remains to be explored.

192: Ghrelin: a step forward in the understanding of somatotroph cell function and
growth regulation.
Dieguez C, Casanueva FF. Eur J Endocrinol  2000 May;142(5):413-7 


193: Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous
ligand for the growth hormone secretagogue receptor.
Hosoda H, Kojima M, Matsuo H, Kangawa K. J Biol Chem  2000 Jul 21;275(29):21995-2000 

Ghrelin, a peptide purified from the stomach, is an endogenous ligand for the
growth hormone secretagogue receptor (GHS-R) and potently stimulates growth
hormone release from the pituitary. Ghrelin is modified with an n-octanoyl group
at Ser(3). This modification is essential for the activity of ghrelin.
Previously, it was not known whether other ligands for GHS-R existed. Here, we
report the purification of the second endogenous ligand for GHS-R from rat
stomach. This ligand, named des-Gln(14)-ghrelin, is a 27-amino acid peptide,
whose sequence is identical to ghrelin except for one glutamine. Southern
blotting analysis under low hybridization conditions indicates that no homologue
for ghrelin exists in rat genomic DNA. Furthermore, genomic sequencing and cDNA
analysis indicate that des-Gln(14)-ghrelin is not encoded by a gene distinct
from ghrelin but is encoded by an mRNA created by alternative splicing of the
ghrelin gene. This is the first example of a novel mechanism that produces
peptide multiplicity. Des-Gln(14)-ghrelin has an n-octanoyl modification at
Ser(3) like ghrelin, which is also essential for its activity.
Des-Gln(14)-ghrelin-stimulated growth hormone releases when injected into rats.
Thus, growth hormone release is regulated by two gastric peptides, ghrelin and
des-Gln(14)-ghrelin.

194: Ghrelin--a new hormone. Rehfeld JF. Ugeskr Laeger  2000 Mar 20;162(12):1751 

195: Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K.
Nature  1999 Dec 9;402(6762):656-60

Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate
the release of growth hormone (GH) from the pituitary. They act through GHS-R, a
G-protein-coupled receptor for which the ligand is unknown. Recent cloning of
GHS-R strongly suggests that an endogenous ligand for the receptor does exist
and that there is a mechanism for regulating GH release that is distinct from
its regulation by hypothalamic growth-hormone-releasing hormone (GHRH). We now
report the purification and identification in rat stomach of an endogenous
ligand specific for GHS-R. The purified ligand is a peptide of 28 amino acids,
in which the serine 3 residue is n-octanoylated. The acylated peptide
specifically releases GH both in vivo and in vitro, and O-n-octanoylation at
serine 3 is essential for the activity. We designate the GH-releasing peptide
'ghrelin' (ghre is the Proto-Indo-European root of the word 'grow'). Human
ghrelin is homologous to rat ghrelin apart from two amino acids. The occurrence
of ghrelin in both rat and human indicates that GH release from the pituitary
may be regulated not only by hypothalamic GHRH, but also by ghrelin.