Poster Presentation Australian & New Zealand Obesity Society 2015 Annual Scientific Meeting

Animals selected for high cortisol responsiveness have reduced melanocortin signalling and increased propensity to obesity (#240)

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. We identified sub-populations of ewes (approximately 10% from each extreme) that have either high (HR) or low (LR) cortisol responses to ACTH (0.2µg/kg). When placed on a high energy diet, HR show a greater propensity to obesity, which is associated with reduced post-prandial thermogenesis in skeletal muscle1 . Hypothalamic appetite-regulating peptides (ARP) exert reciprocal effects on food intake and energy expenditure/thermogenesis. In particular, the pro-opiomelanocortin (POMC) derived neuropeptide alpha melanocyte-stimulating hormone (αMSH) acts on melanocortin receptor 3 (MC3R) and 4 (MC4R) in the brain to suppress food intake and increase thermogenesis. Using in situ hybridization (n=4), we found that, at normal body weight, POMC mRNA expression was similar in HR and LR. HR, however, had reduced gene expression for MC3R (P<0.05) and MC4R (P<0.001) in the paraventricular nucleus (PVN) and this is consistent with a lack of satiety in response to intracerebroventricular infusion of (αMSH) in HR animals2 . Despite, lowered receptor expression in the PVN, the expression of MC3R in the arcuate nucleus and MC4R expression in the lateral hypothalamus, dorsomedial hypothalamus and ventromedial hypothalamus was similar between LR and HR. In order to further characterise inherent differences in the melanocortin system, we used double-immunohistochemistry (n=4), to quantify the melanocortin fibre input on corticotrophin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin neurons of the PVN. The percentage of oxytocin cells receiving input from ɣMSH-labelled fibres was greater (P<0.05) in HR than LR. There was no difference in the number of CRF or AVP cells receiving melanocortin input in LR and HR. In conclusion, enhanced predisposition to obesity in HR is associated with altered melanocortin signalling in the hypothalamus; selection for high cortisol response identifies animals that are resistant to the satiety effects of αMSH.

  1. Lee TK, Clarke IJ, St. John J, Young IR, Leury BL, Rao A, et al. High cortisol responses identify propensity for obesity that is linked to thermogenesis in skeletal muscle. The FASEB Journal. 2014;28(1):35-44.
  2. Hewagalamulage SD, Clarke IJ, Young IR, Rao A, Henry BA. High Cortisol Response to Adrenocorticotrophic Hormone Identifies Ewes with Reduced Melanocortin Signalling and Increased Propensity to Obesity. Journal of Neuroendocrinology. 2015;27(1):44-56.