GHSR agonism increases blood glucose but delays food intake in GHSR hyperresponsive rats.
GHSR agonism in genetically modified rats increased blood glucose levels while delaying feeding response, but the implications for human health are uncertain.
Where it sits
this study against the rest of the hexarelin corpusSummary and findings
This study examined the effects of GHSR agonism on blood glucose levels and feeding behavior in genetically modified rats with enhanced GHSR sensitivity (Ghsr<sup>Q343X</sup>) compared to wild-type controls. The Ghsr<sup>Q343X</sup> rats exhibited a significant increase in blood glucose levels and delayed feeding response following GHSR agonism. No therapeutic claims are made.
Abstract
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<sup>Q343X</sup>) and wild-type littermate controls and examined their acute responses to pharmacological challenges. Consistent with our hypothesis, Ghsr<sup>Q343X</sup> 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<sup>Q343X</sup> rats while they showed unaltered locomotor sensitization to cocaine. At the cellular level, functional studies indicated that the Ghsr<sup>Q343X</sup> 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.