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      Altered Control of the Hypothalamo-Pituitary-Adrenal Axis in Adult Male Rats Exposed Perinatally to Food Deprivation and/or Dehydration

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          Dehydration, a classic homeostatic stressor in rats, leads to a series of well characterized endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. In this study, the hypothesis to be tested was that a 50% maternal food restriction (FR50) in late gestation and lactation may have long-term repercussions on HPA axis responsiveness to dehydration in offspring. For this purpose, we studied HPA axis activity in 4-month-old control (C) and perinatally malnourished male rats after a 72-hour water deprivation period. Furthermore, we investigated the long-lasting effects of perinatal maternal malnutrition on the basal activity of the HPA axis. Under basal conditions, rats exposed to perinatal malnutrition showed reduced body weight, enhanced mineralocorticoid receptor (MR) mRNA levels in CA2 and CA3 hippocampal areas, but decreased glucocorticoid receptor (GR) mRNA levels in CA1, CA3 and dentate gyrus (DG) areas. In contrast, the levels of corticotropin-releasing hormone (CRH) and vasopressin (VP) mRNAs in the hypothalamic paraventricular nucleus (PVN) as well as of VP mRNA in the supraoptic nucleus (SON) were unaffected by maternal undernutrition. Expression of proopiomelanocortin (POMC) in the adenohypophysis was significantly enhanced, whereas prohormone convertase-1 (PC1) was not affected. Perinatal malnutrition reduced absolute adrenal weight but did not affect circulating levels of adrenocorticotropin (ACTH), corticosterone and free corticosterone as well as corticosteroid-binding globulin (CBG) binding capacity. Seventy-two hours of dehydration induced a decrease in body weight and CRH mRNA levels in PVN of controls as well as of FR50 rats, but also led to a rise in plasma corticosterone and free corticosterone without changing CBG binding capacity. Dehydration also induced an increase in adenopituitary POMC (C) and PC1 (FR50), PVN and SON VP (C) and GR in CA1 hippocampal area (FR50) mRNA levels and plasma ACTH (C), but a decrease in MR in DG (C) and GR in CA3 and DG (C) mRNA levels. We conclude that maternal food restriction during the perinatal period affects (1) the adult basal activity of the HPA axis with mainly opposite effects on hippocampal MR and GR gene expression and an increase in adenopituitary POMC gene expression, and (2) the responsiveness to water deprivation in adults. In the latter case, the rise in plasma ACTH levels, adenopituitary POMC gene expression, hypothalamic VP gene expression, and the decrease in hippocampal MR gene expression in DG and GR gene expression in CA3 and DG observed in controls are lacking in FR50 rats. In contrast, drastic adenopituitary PC1 gene expression occurred in FR50 rats but not in control animals.

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          Most cited references 15

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          Regulation of pituitary ACTH secretion during chronic stress.

          Maintenance of adequate levels of response of the hypothalamic-pituitary-adrenal axis during chronic stress is important for survival. Three basic patterns of response can be identified depending on the type of stress: (a) desensitization of ACTH responses to the sustained stimulus, but hyperresponsiveness to a novel stress despite elevated plasma glucocorticoid levels, as occurs in physical-psychological paradigms; (b) no desensitization of ACTH response to the repeated stimulus and hyperresponsiveness to a novel stress, as occurs during repeated painful stress and insulin hypoglycemia; and (c) small and transient increases in ACTH, but sustained elevations of plasma corticosterone and diminished ACTH responses. The level of response of the pituitary corticotroph is determined by differential regulation of the hypothalamic regulators, corticotropin-releasing hormone (CRH) and vasopressin (VP), and the sensitivity of the negative glucocorticoid feedback. While osmotic stimulation increases VP expression in magnocellular neurons of the paraventricular (PVN) and supraoptic nuclei of the hypothalamus, chronic stress paradigms with high pituitary responsiveness are associated with activation of CRH and CRH/VP parvicellular neurons of the PVN, predominantly of the VP-containing population. While moderate increase of CRH output is important for stimulation of POMC transcription, the increase of the VP:CRH secretion ratio appears to be important in maintaining the secretory capacity of the pituitary corticotroph during chronic stimulation. Decreased sensitivity of the glucocorticoid feedback, probably due to interaction of glucocorticoid receptors with transcription factors induced by CRH and VP, is critical for the maintenance of ACTH responses in the presence of elevated plasma glucocorticoid levels during chronic stress. Although both CRH and VP receptors are activated and undergo regulatory variations during chronic stress, only the changes in VP receptor levels are parallel to the changes in pituitary ACTH responsiveness. The inhibitory effect of chronic osmotic stimulation on ACTH secretion in spite of high circulating levels of VP is probably the result of diminished activity of parvicellular PVN neurons and downregulation of pituitary VP receptors. Although the exact interaction between regulatory factors and the molecular mechanisms controlling the sensitivity of the corticotroph during adaptation to chronic stress remain to be determined, it is clear that regulation of the proportional secretion of CRH and VP in the PVN, modulation of pituitary VP receptors, and the sensitivity to feedback inhibition play a critical role.
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            Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age.

             F. Antoni (1993)
            This article summarizes the importance of arginine vasopressin (AVP) in the control of adrenocorticotropin (ACTH) secretion, with special reference to interactions with corticotropin releasing factor (CRF-41), glucocorticoids, and the purported corticotropin release inhibiting peptide atriopeptin. AVP that participates in the regulation of ACTH release at the pituitary level is produced in two main groups of neurons in the hypothalamus: parvicellular cells in the paraventricular nucleus, which also produce CRF-41, and magnocellular neurons in the supraoptic and paraventricular nuclei. The role of the latter in anterior pituitary hormone release has been debated for many years. Evidence generated in the last 5 years shows quite convincingly that AVP released by magnocellular neurons is, in fact, also involved in the control of ACTH. Nevertheless, it is clear that corticotrope cells require CRF-41 to maintain their capacity to secrete ACTH. This is at least due partly to the fact that AVP does not increase proopiomelanocortin mRNA transcription, while CRF-41 is a potent inducer of this gene. New developments in the area of corticotrope cell physiology are discussed, highlighting evidence for dual ACTH secreting pathways in anterior pituitary cells, which may be controlled separately by AVP and CRF-41. Evidence for interactions between ACTH secretagogues and peptidergic as well as glucocorticoid inhibitors of ACTH secretion is reviewed to demonstrate that an important aspect of AVP/CRF-41 dualism may be associated with the ability of the secretagogues to selectively modulate the efficacy of inhibitory factors. Finally, by citing examples from physiological studies on the regulation of ACTH secretion, it is shown how the multicomponent hypothalamic regulatory system operates, emphasizing the considerable signal integrating role of the adenohypophysial corticotrope cell.
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              Structure of the rat pro-opiomelanocortin (POMC) gene.

              The gene encoding pro-opiomelanocortin (POMC) presents unique regulatory features. In particular, glucocorticoids inhibit transcription of the POMC gene in the anterior pituitary, but not in the intermediate pituitary. In order to study the mechanism leading to transcriptional inhibition of POMC by glucocorticoid and the interaction of the glucocorticoid receptor complex with specific DNA sequences along the POMC gene, we have cloned the rat POMC gene and determined its structure. The gene is composed of three exons and appears to be present at a single copy per haploid genome. Besides the usual regulatory signals like 'TATA' and 'CCAAT' boxes, the upstream region contains sequences homologous to known enhancer sequences and to the glucocorticoid receptor binding site observed in glucocorticoid-responsive genes.

                Author and article information

                S. Karger AG
                October 2002
                31 October 2002
                : 76
                : 4
                : 243-253
                aLaboratoire de Neuroendocrinologie du Développement, UPRES-EA 2701 and bLaboratoire d’Endocrinologie des Annélides, UPRES-A 8017 CNRS, Université de Lille 1, Villeneuve d’Ascq, France; cLaboratoire de Physiologie Animale, Université Sidi Mohamed Ben Abdellah, Faculté des Sciences Dhar El Mehrez-Fés, Fés-Atlas, Morocco
                65947 Neuroendocrinology 2002;76:243–253
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 5, Tables: 2, References: 57, Pages: 11
                Dehydration and Osmotic Challenges


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