Ghrelin antagonist [D-Lys3]-GHRP-6 prevents NPY mRNA increase in hypothalamus of feed-restricted ewes
Background
A negative energy balance (NEB), common in situations like feed restriction or high metabolic demand, is known to be detrimental to animal reproduction. The gastrointestinal hormone ghrelin is a proposed link between NEB and reproductive failure, given its role in the hypothalamo-pituitary-gonadal (HPG) axis. When energy is scarce, ghrelin levels rise, which can influence appetite and reproductive signaling. This study investigates whether blocking ghrelin's action at its receptor, the growth hormone secretagogue receptor type 1 (GHS-R1), could mitigate some of the neuroendocrine changes associated with NEB.
Study Design
Two experiments were conducted on 18 ewes, randomly assigned to three groups: Control (fed to maintenance), Feed Restriction (FR; 80% of maintenance), or Ghrelin Antagonist (GA; feed-restricted plus a daily subcutaneous injection of 7.5μg/kg of [D-Lys3]-GHRP-6). Experiment I lasted 30 days, and Experiment II lasted 13 days. Researchers collected plasma to measure hormones and metabolites. In Experiment II, the hypothalamus and ovaries were collected on day 13 to analyze mRNA expression.
Results
In both experiments, ewes in the FR and GA groups lost body weight compared to controls (P < 0.06). Plasma ghrelin was higher in FR and GA groups than in controls (P < 0.01), as were non-esterified fatty acids. In Experiment II, hypothalamic Kiss1-R mRNA expression was greater in FR ewes (P < 0.01) and tended to be greater in GA ewes (P = 0.10) compared to controls. GhRH mRNA expression was greater in the GA group (P = 0.04) and tended to be greater in the FR group (P = 0.07) versus controls.
The key finding was in neuropeptide Y (
NPY) expression:NPYmRNA was significantly greater in the Feed Restriction group than in the Control group (P = 0.03) but was not significantly elevated in the Ghrelin Antagonist group, which only tended to be greater than controls (P = 0.06). This suggests the antagonist blunted theNPYresponse to feed restriction.
Key Findings
- Ghrelin antagonist [D-Lys3]-GHRP-6 prevented a significant increase in hypothalamic NPY mRNA expression in feed-restricted ewes.
- Feed restriction increased NPY mRNA expression compared to controls (P = 0.03).
- Both feed-restricted groups (FR and GA) had higher plasma ghrelin concentrations than controls (P < 0.01).
- Kiss1-R mRNA expression was significantly greater in feed-restricted ewes compared to controls (P < 0.01).
- GhRH mRNA expression was significantly greater in the ghrelin antagonist group compared to controls (P = 0.04).
Why It Matters
This research suggests that blocking ghrelin receptors can specifically modulate the hypothalamic response to energy deficit, particularly by preventing the upregulation of NPY, a potent appetite stimulant. For researchers or biohackers exploring metabolic control during caloric restriction, this highlights a specific mechanism that can be targeted. While this is an animal study in ewes, it provides a rationale for investigating ghrelin antagonists to manage neuroendocrine adaptations to diet-induced stress. Blocking ghrelin may prevent some of the compensatory hunger signals, like increased NPY, that arise during calorie restriction, potentially making diets more sustainable. Further research is needed to see if this translates to humans and affects reproductive outcomes long-term.
