Vagal Afferent Mediates the Anorectic Effect of Peripheral Secretin

published_or_final_versio

Integrated life science education in Bachelor of Nursing and Bachelor of Chinese Medicine at The University of Hong Kong

poster presentation no. PP54published_or_final_versio

Reduced sodium appetite in water-deprived SCT-deficient mice

Plenary Lecture - Neuropeptides and peptidergic neurons: P1-142The 7th International Congress of Neuroendocrinology (ICN2010), Rouen, France, 11-15 July 2010

Actions of secretin on the hypothalamic magnocellular neurons: Implications for the control of body water homeostasis

For the last 100 years, secretin has been extensively studied for its hormonal effects in the gastrointestinal tract. Recent observation by our group that this classical gastrointestinal hormone is readily releasable from hypothalamic neurons upon K+ -evoked depolarization suggested a potential influence of this peptide on the neuronal activity within this brain region. We hereby showed that intracerebroventricularly-injected secretin could elevate c-fos and vasopressin (VP) gene expression in the magnocellular subdivision of the Paraventricular Nucleus as well as throughout the Supraoptic Nucleus. In addition, it could also enhance, through a cAMP/PKA-dependent pathway, the basal release of VP from the hypothalamic explants. Together with the fact that secretin is expressed at high concentrations in the circumventricular subfornical organ, which contains osmoreceptor cells that regulate the plasma osmolality, as well as its releasing ability from the somatodendritic and axonal compartments of the magnocellular neurons via a TTX-sensitive and Ca2+-dependent mechanism, it is speculated that locally released secretin in the hypothalamo – neurohypophysial system could act in autocrine and/or paracrine manners via its G protein-coupled receptor to modulate osmoregulation.link_to_subscribed_fulltex

Secretin: A pleiotrophic hormone

Secretin holds a unique place in the history of endocrinology and gastrointestinal physiology, as it is the first peptide designated as a hormone. During the last century since its first discovery, the hormonal effects of secretin in the gastrointestinal tract were extensively studied, and its principal role in the periphery was found to stimulate exocrine secretion from the pancreas. Recently, a functional role of secretin in the brain has also been substantiated, with evidence suggesting a possible role of secretin in embryonic brain development. Given that secretin and its receptors are widely expressed in multiple tissues, this peptide should therefore exhibit pleiotrophic functions throughout the body. The present article reviews the current knowledge on the central and peripheral effects of secretin as well as its therapeutic uses. © 2006 New York Academy of Sciences.link_to_subscribed_fulltex

Vasopressin-independent mechanisms in controlling water homeostasis

The maintenance of body water homeostasis depends on the balance between water intake and water excretion. In the kidney, vasopressin (Vp) is a critical regulator of water homeostasis by controlling the insertion of aquaporin 2 (AQP2) onto the apical membrane of the collecting duct principal cells in the short term and regulating the gene expression of AQP2 in the long term. A growing body of evidence from both in vitro and in vivo studies demonstrated that both secretin and oxytocin are involved as Vp-independent mechanisms regulating the renal water reabsorption process, including the translocation and expression of AQP2. This review focuses on how these two hormones are potentially involved as Vp-independent mechanisms in controlling water homeostasis. © 2009 Society for Endocrinology.link_to_OA_fulltex

Secretin: A potential neurosecretory factor regulating body water homeostasis.

Akira Arimura Young Investigator Award Lecturepp. 305-347 of this journal issue entitled: Abstracts of the 8th International Symposium on VIP, PACAP and Related PeptidesSecretin, originally isolated from the upper intestinal mucosal extract, is a classical gastrointestinal hormone that has recently implicated to play a neuromodulatory role in higher centers, including cerebellumand hippocampus. On the other hand, its functions in the hypothalamo-neurohypophysial axis have not fully appreciated. Using secretin receptor-null (SCTR−/−) mice, we showed previously that secretin exerts peripheral functions in the kidney, where it modulates the process of renal water reabsorption by stimulating the expression and trafficking of aquaporin-2. Now, we provide evidence to show the activity of secretin at the hypothalamo-pituitary level to regulate body water homeostasis by demonstrating (1) the presence of secretin and its receptor in the hypothalamo-neurohypophysial axis; (2) secretin-induced activation of cfos and vasopressin (Vp) expression in the magnocellular neurons within Paraventricular (PVN) and Supraoptic Nuclei (SON); (3) the in vitro and in vivo stimulatory effects of secretin on Vp secretion; (4) augmentations of secretin and its receptor expression in the hypothalamus and pituitary under water deprivation; (5) TTX- and Cd2+-dependent release of secretin from the posterior pituitary during plasma hyperosmolality; and (6) electrical stimulation of SON and PVN led to a pulsatile release of secretin in peripheral circulation measured in the jugular vein. Taken together, these results revealed that secretin is a novel neurosecretory hormone from the neurohypophysis to modulate body fluid and electrolyte homeostasis

Endogenous release of secretin from the hypothalamus

Previous studies demonstrated that secretin could be released from the cerebellum, where it exerts a facilitatory action on the GABAergic inputs into the Purkinje neurons. In the present article, we provide evidence of the endogenous release of secretin in the hypothalamus and the mechanisms underlying this release. Incubation of the hypothalamic expiants with KCl induces the release of secretin to 4.35 ± 0.45-fold of the basal level. This K +-induced release was tetrodotoxin and cadmium sensitive, suggesting the involvement of voltage-gated sodium and calcium channels. The use of specific blockers further revealed the involvement of L-, N-, and P-type high voltage-activated (HVA) calcium channels. Results present in the current article provide further and more solid evidence of the role of secretin as a neuropeptide in the mammalian central nervous system. © 2006 New York Academy of Sciences.link_to_subscribed_fulltex

Actions of secretin on the hypothalamic magnocellular neurons: Implications for the control of body water homostasis

pp. 133-188 of this journal issue entitled: Abstracts of the 7th International Symposium on VIP, PACAP and Related Peptides. Rouen, France. September 11-14, 2005For the last 100 years, secretin has been extensively studied for its hormonal effects in the gastrointestinal tract. Recent observation by our group that this classical gastrointestinal hormone is readily releasable from hypothalamic neurons upon K+-evoked depolarization suggested a potential influence of this peptide on the neuronal activity within this brain region. We hereby showed that intracerebroventricularly-injected secretin could elevate c-fos and vasopressin (VP) gene expression in the magnocellular subdivision of the Paraventricular Nucleus as well as throughout the Supraoptic Nucleus. In addition, it could also enhance, through a cAMP/PKA-dependent pathway, the basal release of VP from the hypothalamic explants. Together with the fact that secretin is expressed at high concentrations in the circumventricular subfornical organ, which contains osmoreceptor cells that regulate the plasma osmolality, as well as its releasing ability from the somatodendritic and axonal compartments of the magnocellular neurons via a TTX-sensitive and Ca2+-dependent mechanism, it is speculated that locally released secretin in the hypothalamo– neurohypophysial system could act in autocrine and/or paracrine manners via its G protein-coupled receptor to modulate osmoregulation.link_to_subscribed_fulltex

A putative role of secretin to regulate water homeostasis

Secretin was first discovered as a gastrointestinal hormone a century ago, and to date, the role of secretin in regulating functions of exocrine pancreas is firmly established. The notion of secretin as a neuropeptide has recently received a revived attention, our group proposed that secretin functions as a retrograde messenger in the cerebellum to facilitate GABA release from the basket cells. In this report, the role of secretin in the hypothalamo – pituitary axis was investigated. We demonstrated that, upon potassium-evoked depolarization, secretin could be released in the hypothalamus and pituitary. In addition, secretin and its receptor were found to co-express with vasopressin in SON and PVN of the hypothalamus as well as the posterior pituitary. In the SON, intracerebroventricular administration of secretin was able to activate vasopressin gene expression via the cAMP/c-fos pathway. To examine further the physiologic functions of secretin, secretin receptor gene knockout mice (deletion of exon 10) were produced and phenotypic analyses revealed that secretin receptor knockout mice (SCTR / ) consistently had full and distended urinary bladders. These mutants drank and urinated more, while the osmolality, as well as the concentrations of Na+ , K+ , Cl , urea and creatinine, were lowered than those of the wild-types. Intraperitoneal injection of dDAVP suggested a normal urine-concentrating ability by vasopressin in SCTR / . The phenotypes observed were likely due to a reduced expression of the water channel aquaporin-3 in kidney as shown in real-time PCR and Western blot analyses. Based on these findings, we propose a role of secretin in modulating water homeostasis at multiple levels including the hypothalamus, posterior pituitary and kidney.link_to_subscribed_fulltex