Metabolic signalling and neuroendocrine stress responses in pregnancy

The hypothalamo-pituitary-adrenal (HPA) axis is hyporesponsive during late pregnancy to emotional, physical and metabolic signals. This is due to reduced responsiveness of the parvocellular paraventricular nucleus (pPVN) corticotrophin releasing hormone (CR11) and arginine vasopressin (AVP) neurones. Major adjustments in metabolic regulation during late pregnancy will help ensure a successful outcome. These include increased appetite and reduced energy expenditure during exposure to a stress, to which reduced neuroendocrine stress responses may contribute. Glucocorticoids have a key role in mobilising energy in response to acute stress, and have longer-term actions in the regulation of fat storage. I investigated the relationship between the HPA axis and endocrine factors relating to adipose tissue storage and appetite regulation during late pregnancy in rats. The responsiveness of the hypothalamic neurones regulating ACTH and hence corticosterone responses to insulin induced hypoglycaemia (IIH) and the orexigenic peptides NPY, orexin and ghrelin was investigated with particular focus on the mechanisms involved in restraining these responses during late pregnancy. IIH increased ACTH secretion similarly in both virgin and pregnant rats. Unlike most stressors IIH did not stimulate parvocellular CRH mRNA expression in pPVN neurones but it did increase AVP mRNA expression. The responsiveness of the HPA axis to the orexigenic peptides ghrelin, orexin and NPY given by i.e.v. injection was markedly reduced during late pregnancy. This was at least partly a result of reduced activation of the pPVN neurones, as revealed by reduced stimulation of Fos expression in the pPVN compared with virgin rats given these peptides. ACTH secretory responses were also strongly attenuated in late pregnant rats. In contrast all three orexigenic peptides increased food intake to a similar level in both virgin and pregnant rats. Thus neuroendocrine stress responses to central administration of orexin, NPY and ghrelin are absent during late pregnancy whilst ingestive behavioural responses remain intact. Changes in brain circuitry regulating appetite during late pregnancy were shown by increased Fos activation in the lateral hypothalamic area (LPIA), ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH). Supraoptic and magnocellular PVN oxytocin responses to centrally administered NPY were reduced during late pregnancy. Endogenous opioids are involved in the attenuation of HPA axis responses to orexin and NPY during late pregnancy since pre-treatment with the opioid receptor antagonist naloxone reinstated the ACTH response and restored CRH and AVP mRNA responses. Naloxone administration revealed that endogenous opioids facilitate NPY-induced feeding in both virgin and late pregnant rats, but more importantly in late pregnant rats. Naloxone restored a Fos response in the PVN and SON in response to NPY in late pregnant rats indicating that oxytocin neurone responses to NPY are suppressed by endogenous opioids. Basal blood glucose levels were lower in late pregnant rats than in virgins. Ghrelin increased blood glucose levels similarly in both virgin and pregnant rats, whilst NPY and orexin increased blood glucose in only the virgin rats. In conclusion, neuroendocrine stress responses to orexin, ghrelin and NPY are reduced in pregnant rats, and this was shown for orexin and NPY to be due to endogenous opioid restraint. Endogenous opioid mechanisms have opposite effects on neuroendocrine stress responses and feeding, which will enhance energy availability for the fetuses at this time. Intact FIPA axis responses to IIH will ensure continued glucose supply.

Grantor dc:publisher

The University of Edinburgh

Year dc:date.issued

2007

Author dc:creator

• Bales, Juliana

Handle dc:identifier.uri

http://hdl.handle.net/1842/29065

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/29065