<scp>GHSR</scp> agonism increases blood glucose but delays food intake in <scp>GHSR</scp> hyperresponsive rats

Severe calorie restriction in mouse models has highlighted the crucial role of the ghrelin system in maintaining glycemia and promoting survival. We hypothesized that if ghrelin acts as a survival signal, enhancing the responsivity of the GH secretagogue receptor (GHSR) should favor GHSR protective responses. To test this, we used rats with genetically enhanced GHSR sensitivity (Ghsr^Q343X) and wild-type littermate controls and examined their acute responses to pharmacological challenges. Consistent with our hypothesis, Ghsr^Q343X rats, despite normal glucose and insulin tolerance, exhibited a significant increase in blood glucose in response to GHSR agonism, accompanied by elevated counter-regulatory hormones including corticosterone. Concurrently, these rats displayed a notable decrease in locomotor activity and delayed feeding response. Also, GHSR agonism partially altered the cocaine-induced hyperlocomotion of Ghsr^Q343X rats while they showed unaltered locomotor sensitization to cocaine. At the cellular level, functional studies indicated that the Ghsr^Q343X mutation prolongs ghrelin-induced GHSR-G protein canonical signaling. Altogether, in a model of increased GHSR sensitivity, GHSR agonist stimulation was sufficient to promote a robust blood glucose increase, while the acute feeding response was delayed in a context of unexpected hypolocomotor response. This mechanism may have implications for severe states of undernutrition such as restrictive anorexia nervosa.