ENEA 2002, Abstracts of Prize Lectures
ENEA Young Investigator Award
for Basic Research 2002
The pituitary gland: the crucial crossroad
Pagotto U
Endocrine Unit and Center for Applied Biomedical Research (C.R.B.A.),
S.Orsola-Malpighi Hospital, Bologna, Italy
The pituitary gland represents a unique model for studying the
physiological mutual interplay between hypothalamic and suprahypothalamic
neuropeptides and peripheral hormones. Both pituitary secretion
and growth are also closely regulated by a complex autocrine and
paracrine interaction played by intrahypophyseal hormones, neuropeptides,
cytokines and growth factors. The fine-tuned balance between secretion,
cell division, differentiation and apoptosis of the normal pituitary
gland can very often be disarranged by alterations which can lead
to tumoral development and progression.
The elucidation of some processes leading to pituitary adenoma formation
and the description of putative pharmacological tools limiting the
uncontrolled growth or the hypersecretion of these neoplasms will
be discussed in the light of our recent findings. Moreover, in order
to stress the role of the pituitary gland as a unique biological
model, we will demonstrate how the knowledge of the pituitary mechanisms
involved in its physiology and pathophysiology may anticipate and
favor further studies related to other systems.
ENEA Young Investigator Award
for Clinical Research 2002
From Cyril Bowers to Prader-Willi: Ghrelin
and human energy homeostasis
Tschöp M.
Department of Pharmacology, German Institute of Human Nutrition,
Potsdam-Rehbrücke, Germany
In the late seventies, C. Bowers from New Orleans discovered novel
agents stimulating growth hormone secretion and called them growth
hormone secretagogues (GHS). Based on experiments showing that enkephalin
analogs were weakly active in releasing GH from rat pituitary in
vitro, more potent GHS were designed, based on structural and chemical
observations and calculations. The existence of an endogenous endocrine
system behind these observations was confirmed 1996 when the growth
hormone secretagogue receptor (GHS-R) was cloned.
Two years ago, Dr. Kojima's brilliant work provided the final proof
of C. Bowers's vision by identifying the novel hormone ghrelin as
an active endogenous ligand of the GHS-R. Surprisingly, ghrelin
soon turned out to be a pleiotropic hormone with multiple physiological
roles. Based on the fact that ghrelin induces adiposity in rodents
and triggers hunger and increased food intake in humans, a role
for ghrelin in the neuroendocrine control of energy balance soon
became the predominant focus of ghrelin research.
Ghrelin is mainly produced and secreted by the human stomach in
response to an acutely (fasting) or chronically (cachexia) negative
energy balance, while circulating postprandial levels and plasma
ghrelin concentrations of obese individuals are relatively low.
While we hypothesize that the latter observations reflect an integration
of ghrelin in compensatory mechanisms of complex neuroendocrine
circuits balancing energy homeostasis, recent findings indicate
possible clinical relevance of ghrelin as a hunger hormone. Ebbing
ghrelin secretion following gastric bypass surgery in morbidly obese
patients might be responsible, at least in part, for the outstanding
efficiency of this bariatric procedure, while impressive hyperghrelinemia
has been identified as a potential cause for hyperphagia and obesity
in patients with Prader-Willi syndrome. While the majority of published
data are consistent with the hypothesis that ghrelin is a physiologically
relevant regulator of human energy homeostasis, proof of this hypothesis
will require intervention studies using agents that block ghrelin
secretion or action.
Ipsen Foundation Prize Endocrine Communication and
Regulation
Corticotropin releasing factor family
of ligands and their receptors
Vale,W.*, Bale, T.*, Li, C.*, Reyes, T.*, Perrin, M.*, Jamieson,
P.*, Chen, A*, Brar. B.*, Vaughan, J.*, Rivier, J.*, Peterson, K.,
Contarino, A.†, Valdez, G.†, Zorrilla, E.† , Koob,
G.†, Lee, K-F.* and Sawchenko, P.*
*The Salk Inst., Univ. of California, San Diego and
†Scripps Research Inst., La Jolla, CA
Corticotropin releasing factor (CRF) is the key neuroregulator
of the hypothalamic-pituitary-adrenal cortical axis (HPA) and mediates
numerous complementary stress-related endocrine, autonomic and behavioral
responses. CRF antagonists block many stress-induced responses in
experimental animals and perturbations of the CRF system or HPA
have been reported in human affective disorders.
The actions of CRF are mediated by two heptahelical receptors derived
from two genes, each of which have alternative splice variants.
The two receptor types differ with respect to anatomic distribution
and pharmacologic specificity. Mice null for CRF-R1 exhibit reduced
basal and stress-induced HPA activity and diminished behavioral
responses to anxiogenic stimuli. Mice null for CRF-R2 have been
developed and found to exhibit endocrine and behavioral hyper-responsiveness
to anxiogenic stimuli, revealing potential anxiolytic roles for
CRF-R2 and cognate ligands.
By contrast, other experiments involving direct administration
of R2 agonists and antagonists into specific brain regions have
revealed anxiogenic-like roles for CRF-R2 as well. The mammalian
peptide, urocortin (Ucn) was identified in rat brain and human genome
as a potential ligand for CRF-R2 and found to have high affinity
for and potent biological actions on both CRF-R1 and CRF-R2. The
coincidence of Ucn-like immunoreactive fibers with some but not
all sites of CRF-R2 expression supported the hypothesis that urocortin
is an endogenous ligand for a subset of CRF-R2; however, this also
raised the possibility of there being additional ligands.
Recently, our group and Hsu and Hsueh have identified two new human
genes, Ucn II and Ucn III (stresscopin). Our group has also cloned
the mouse orthologues of Ucn II and Ucn III. Peptides deduced from
the Ucn II and Ucn III precursors are highly selective for CRF-R2,
inhibiting anxiety and appetite, delaying gastric emptying, decreasing
peripheral resistance and stimulating cardiac output. In the rodent,
urocortin, urocortin II and III mRNA's and peptides display unique
CNS and peripheral distributions. Specifying the contributions of
the various members of the CRF family of ligands and receptors to
the maintenance of homeostasis and to the "allostatic load"
associated with stress may improve our ability to manage affective
and other disorders.
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