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.