Ghrelin

Ghrelin is a 28-amino acid peptide hormone predominantly secreted by endocrine X/A-like cells (P/D1 cells) of the gastric fundus. Its defining feature is an octanoyl (n-octanoic acid) modification on Ser3, which is essential for its binding to and activation of the growth hormone secretagogue receptor type 1a (GHS-R1a).

Ghrelin was discovered in 1999 by Kojima et al. as the endogenous ligand for GHS-R1a — a receptor that had been identified years earlier as the target for synthetic growth hormone secretagogues like GHRP-2 and GHRP-6. This discovery elegantly explained the mechanism by which all earlier GHSPs worked, and identified the stomach as a major endocrine organ in the GH axis.

**Two key functions:**

1. **GH Secretagogue**: Ghrelin acts synergistically with GHRH in the hypothalamus to amplify GH pulses from the anterior pituitary. Fasting-induced ghrelin rises coordinate with GHRH to produce larger nocturnal GH pulses and enhance the GH response to exercise.

2. **Orexigenic hormone**: Ghrelin is the only known circulating orexigen (appetite stimulant). Its levels rise before meals and fall after eating. It activates NPY/AgRP neurons in the hypothalamic arcuate nucleus to drive food-seeking behavior. Its antagonist LEAP-2 (also documented in this database) is the counter-regulatory signal.

The entire family of synthetic GHSPs — GHRP-2, GHRP-6, ipamorelin, hexarelin, and MK-677 — were designed to mimic or improve upon ghrelin's properties. They share GHS-R1a agonism but differ in selectivity (cardiac receptors, appetite effects), half-life, and potency.

Research applications include: GH deficiency research, cardiac ischemia protection, cancer cachexia, sarcopenia, GI motility disorders (gastroparesis), and metabolic disease (ghrelin/LEAP-2 ratio as a metabolic biomarker).