# GHSR agonism increases blood glucose but delays food intake in GHSR hyperresponsive rats

## TL;DR

This study shows that increased sensitivity to the ghrelin receptor leads to higher blood sugar and delayed eating in response to a drug that activates the receptor.

## Contribution

The study reveals new insights into how GHSR hyperresponsiveness affects glucose and feeding behaviors.

## Key findings

- GHSR agonism significantly increased blood glucose in hyperresponsive rats.
- Hyperresponsive rats showed delayed feeding and reduced locomotor activity.
- The Ghsr Q343X mutation prolonged ghrelin-induced signaling.

## 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
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.

GHSR agonism increases blood glucose, inhibits locomotor activity and delays food intake in GHSR hyperresponsive rats.