Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Differences in cortisol response to adrenocorticotropin (ACTH) reflect an innate alteration of the set-point of the hypothalamo-pituitary-adrenal (HPA) axis that is maternally inherited (#21)

Sakda D Hewagalamulage 1 , Iain J Clarke 1 , Belinda A Henry 1
  1. Department of Physiology, Monash University, Building 13F, Vic 3800, Australia
Within any population, the cortisol response to ACTH covers a considerable range. High responders (HR) exhibit a heightened cortisol secretory response to stress or ACTH, whereas this response is attenuated in low responders (LR).  We administered 0.2µg/kg ACTH (i.v.) to 100 female sheep and selected animals at the 10% extremes, to represent HR and LR. These animals show metabolic and behavioural differences that lead to an obesity prone phenotype in HR1 . In the present study we aimed to characterise the HPA axis in HR and LR and to identify factors that underlie their differing cortisol responses to ACTH. Hypothalami, pituitaries and adrenals were collected from non-stressed HR and LR ewes (n=4). Expression of genes for corticotropin-releasing factor (CRF), arginine vasopressin (AVP), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) were measured by in situ hybridisation in the paraventricular nucleus of the hypothalamus and pro-opiomelanocortin (POMC) gene expression was measured in the pituitary. Expression of CRF (P<0.05), AVP (P<0.01) and POMC (P<0.05) was higher in HR, with no differences in GR and MR expression. In adrenals, PCR analysis showed that expression of the ACTH receptor and a range of synthetic enzymes in the steroidogenic pathway were similar in HR and LR (n=5). Adrenal weights, the cortex:medulla ratio and adrenal cortisol content were similar in LR and HR. To determine whether cortisol responsiveness is heritable, HR and LR (n=5) ewes were mated to a single ram. Cortisol responses to ACTH were greater (P<0.05) in offspring of HR mothers than in those of LR mothers. In conclusion, HR and LR display innate differences in the steady-state expression of CRF, AVP and POMC, indicating a different set-point of the HPA axis in the hypothalamus and pituitary. Preliminary breeding studies indicate that these differences are maternally inherited.
  1. Lee TK, Clarke IJ, St. John J, Young IR, Leury BL, Rao A, Andrews ZB, and Henry BA. High cortisol responses identify propensity for obesity that is linked to thermogenesis in skeletal muscle. The FASEB Journal 28: 35-44, 2014.