Ghrelin

Ghrelin is a 28-amino acid peptide hormone discovered in 1999, primarily produced by specialized cells in the stomach lining. Often called 'the hunger hormone,' ghrelin is the primary physiological signal that triggers appetite before meals and promotes food-seeking behavior.

Beyond appetite, ghrelin is also a potent growth hormone secretagogue—it was actually discovered while searching for the natural ligand of the growth hormone secretagogue receptor (GHSR-1a). This dual role connects hunger with growth and energy storage, coordinating the body's response to food availability.

Understanding ghrelin is essential for understanding GH-releasing peptides (GHRPs) like Ipamorelin, GHRP-6, and MK-677—they're all ghrelin mimetics designed to activate the same receptor. Ghrelin research continues for cachexia, anorexia, and other conditions where appetite restoration could be therapeutic.

Ghrelin exerts its effects primarily through the growth hormone secretagogue receptor (GHSR-1a), affecting multiple systems.

Appetite Regulation

In the hypothalamus, ghrelin activates hunger-promoting neurons (NPY/AgRP) and inhibits satiety neurons (POMC). This shifts the balance toward hunger, food-seeking, and increased food intake. Ghrelin also activates reward pathways, making food more appealing.

Growth Hormone Release

GHSR-1a on pituitary somatotrophs mediates ghrelin's GH-releasing effects. Ghrelin is a potent GH secretagogue, working synergistically with GHRH for robust GH pulses.

Gastric Effects

Ghrelin increases gastric motility and acid secretion, preparing the digestive system for incoming food.

Unique Structure

Ghrelin requires acylation (an octanoyl fatty acid on serine-3) for receptor activation. This unusual modification is critical for biological activity.

Since its discovery, ghrelin has been extensively studied for appetite regulation and potential therapeutic applications.

Physiology Research

Studies established ghrelin as the primary pre-meal hunger signal, with levels rising before and falling after meals. Gastric bypass surgery reduces ghrelin by removing producing tissue, contributing to reduced appetite post-surgery.

Therapeutic Research

Clinical trials have explored ghrelin and ghrelin mimetics for cachexia (cancer, heart failure, COPD-related wasting), showing ability to increase appetite and food intake. Research in anorexia nervosa has explored whether ghrelin signaling dysfunction contributes to the disease.

Ghrelin research dosing has varied by application and study design.

Research Context

Clinical studies have used IV infusion (for acute GH-release studies) or subcutaneous injection (for appetite studies). Doses have ranged from 1-5 mcg/kg depending on the endpoint studied.

Practical Limitations

Ghrelin's short half-life and the need for acylation make it less practical than synthetic ghrelin mimetics like Ipamorelin or MK-677 for sustained effects.

As an endogenous hormone, ghrelin at physiological levels is inherently safe. Supraphysiological administration carries considerations.

Expected Effects

• Increased hunger (primary effect)
• GH release
• Potential blood glucose effects

Considerations

Chronic elevation could theoretically promote weight gain and metabolic changes, though this would be the therapeutic goal in cachexia applications.