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.
- 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.