Des-Acyl Ghrelin and Ghrelin O-Acyltransferase Regulate Hypothalamic-Pituitary-Adrenal Axis Activation and Anxiety in Response to Acute Stress

Romana Stark, Vanessa V Santos, Bram Geenen, Agustina Cabral, Tara Dinan, Jacqueline A Bayliss, Sarah H Lockie, Alex Reichenbach, Moyra B Lemus, Mario Perello, Sarah J Spencer, Tamas Kozicz, Zane B Andrews

Ghrelin exists in two forms in circulation, acyl ghrelin and des-acyl ghrelin, both of which have distinct and fundamental roles in a variety of physiological functions. Despite this fact, a large proportion of papers simply measure and refer to plasma "ghrelin" without specifying the acylation status. It is therefore critical to assess and state the acylation status of plasma ghrelin in all studies. In this study we tested the effect of des-acyl ghrelin administration on the HPA axis and on anxiety-like behaviour of mice lacking endogenous ghrelin, and in GOAT KO mice that have no endogenous acyl ghrelin and high endogenous des-acyl ghrelin. Our results show des-acyl ghrelin produces an anxiogenic effect under non-stressed conditions but this switches to an anxiolytic effect under stressed. Des-acyl ghrelin influences plasma corticosterone under both non-stressed and stressed conditions although c-fos activation in the PVN is not different. By contrast, GOAT KO are anxious under both non-stressed and stressed conditions although this is not due to corticosterone release from the adrenals but rather from impaired feedback actions in the PVN, as assessed by c-fos activation. These results reveal des-acyl ghrelin treatment and GOAT deletion have differential effects on the HPA axis and anxiety-like behaviour, suggesting that anxiety-like behaviour in GOAT KO mice is not due to high plasma des-acyl ghrelin.