Ghrelin
Endogenous 28-amino acid orexigenic hormone and GH secretagogue; the natural ligand for GHS-R1a that explains why ipamorelin, MK-677, GHRP-2, and GHRP-6 work.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | Lenomorelin (INN), "hunger hormone" |
| Category | GH Axis / Endogenous reference peptide |
| Sequence | GSSFLSPEHQRVQQRKESKKPPAKLQPR (28 aa; octanoylated at Ser3) |
| Molecular Weight | ~3371 Da (acylated form) |
| Molecular Formula | C₁₄₉H₂₄₉N₄₅O₄₂ |
| PubChem CID | 10096344 |
| Administration | Not used therapeutically (IV/SubQ in research only) |
| Typical Dose Range | Not applicable — endogenous reference; research doses: 1-5 mcg/kg IV |
| Half-Life | ~30 minutes (acyl-ghrelin); des-acyl ghrelin ~10 min |
| Storage | Research-grade: lyophilized, -20 C |
| FDA Status | Not a drug product; endogenous hormone. No FDA-approved ghrelin products (analogs/mimetics are separate) |
| WADA Status | GH secretagogues are prohibited (S2 class) |
Mechanism of Action
Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a), a G-protein coupled receptor (GPCR) that couples primarily to Gq/11 signaling. Ghrelin was discovered in 1999 by Kojima et al. in rat stomach extracts, resolving the decade-long search for the natural ligand of the previously orphaned GHS-R (PMID-10604470).
Ghrelin's essential structural feature is the octanoyl (C8:0) fatty acid modification at Ser3, catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). This acylation is absolutely required for GHS-R1a binding and GH-releasing activity. Without it, the peptide is called "des-acyl ghrelin" which may have distinct biological activities through unknown receptors.
GH release pathway: Ghrelin binds GHS-R1a on pituitary somatotrophs, activating Gq → PLC → IP3/DAG → intracellular calcium release → GH vesicle exocytosis. Critically, ghrelin acts synergistically with GHRH — ghrelin amplifies the GH pulse initiated by GHRH rather than acting independently. This synergy occurs because GHRH signals through Gs/cAMP while ghrelin signals through Gq/calcium, and both pathways converge on GH secretion (PMID-15788704).
Appetite pathway: Ghrelin crosses the blood-brain barrier and activates GHS-R1a on NPY/AgRP neurons in the arcuate nucleus of the hypothalamus, stimulating appetite and food-seeking behavior. This is independent of GH release. Ghrelin is the only known circulating orexigenic hormone — it rises before meals and falls after eating (PMID-22385874).
Other functions: Gastric motility stimulation (via vagal afferents), gastric acid secretion, cardiovascular effects (vasodilation, increased cardiac output), glucose metabolism modulation, bone metabolism, reward processing, and stress/anxiety modulation.
Key Research Areas
- GH secretagogue receptor biology — Ghrelin discovery explained the mechanism of synthetic GH secretagogues (PMID-10604470)
- Appetite and energy homeostasis — Only known circulating hunger hormone; key regulator of meal initiation (PMID-22385874)
- GH axis synergy — Ghrelin + GHRH synergy explains why CJC-1295/Ipamorelin combinations are superior (PMID-15788704)
- Cachexia/anorexia — Ghrelin analogs explored for cancer cachexia, COPD, heart failure-related wasting
- Gastroparesis — Ghrelin's prokinetic effects studied for functional GI disorders
- GHS-R constitutive activity — Receptor signals at ~50% maximal without ligand, relevant for inverse agonist drug design
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | Limited | Mostly proof-of-concept studies for cachexia, gastroparesis |
| Systematic reviews | Several | Appetite, GH secretion, gastroparesis reviews |
| Human observational | Many | Endocrine physiology studies |
| Animal in vivo | Extensive | Foundation of ghrelin biology |
| In vitro | Extensive | Receptor pharmacology, signaling |
Clinical Applications
- Sarcopenia — Ghrelin axis relevant to muscle-wasting conditions
- Fat Loss — Ghrelin physiology context for weight management
- Weight Management — Understanding hunger hormone in obesity
Protocols Using This Peptide
Ghrelin itself is not used in clinical protocols. Its receptor (GHS-R1a) is the target for:
- GH Optimization Protocol — Via ipamorelin, MK-677
- Wolverine Stack Protocol — Indirect relevance via GH axis
Ageless Peps Products
Ghrelin is an endogenous hormone and is NOT sold as a product. The following Ageless Peps products work through ghrelin's receptor (GHS-R1a):
- Ipamorelin — Selective GHS-R1a agonist (most selective synthetic ghrelin mimetic)
- MK-677 — Oral non-peptide GHS-R1a agonist
- CJC-1295 NO DAC / Ipamorelin blend — Combines GHRH analog + ghrelin mimetic for synergistic GH release
Dosing Reference
Research Dosing (not clinical use)
| Route | Dose Range | Frequency | Duration | Source |
|---|---|---|---|---|
| IV bolus | 1-5 mcg/kg | Single dose (research) | Acute studies | Various research protocols |
| SubQ | 1-3 mcg/kg | Variable | Research only | Preclinical studies |
Cycling
Not applicable — ghrelin is an endogenous hormone with pulsatile secretion (rises pre-prandially, falls post-prandially).
Contraindications & Safety
- Contraindications: Not applicable (endogenous hormone; not used therapeutically)
- Side effects of exogenous administration: Hunger, increased food intake, mild hyperglycemia, GH elevation
- Drug interactions: N/A for endogenous; GHS-R1a agonists may interact with somatostatin analogs (opposing effects on GH)
- Pregnancy/nursing: Endogenous ghrelin plays role in fetal development
- Special populations: Ghrelin levels are altered in anorexia nervosa (elevated), obesity (reduced), post-bariatric surgery (reduced)
Synergistic Combinations
Understanding ghrelin's synergy with GHRH explains clinical peptide combinations:
- Ghrelin pathway (Ipamorelin) + GHRH pathway (CJC-1295 NO DAC) → Synergistic GH release (the basis for CJC/Ipamorelin blend)
- Ghrelin pathway (Ipamorelin) + GHRH pathway (Tesamorelin) → Synergistic GH release (Tesamorelin/Ipamorelin blend)
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| 10604470 | Ghrelin Discovery: GH-Releasing Peptide from Stomach (Nature) | 1999 | In vitro / Animal |
| 22385874 | Ghrelin: Physiological Significance and Clinical Applications | 2012 | Narrative Review |
| 15788704 | Ghrelin: Structure and Function (Endocrine Reviews) | 2004 | Narrative Review |
References
- PMID-10604470 — Kojima et al., Ghrelin discovery, Nature 1999
- PMID-22385874 — Stengel & Tache, Ghrelin physiology review, Curr Pharm Des 2012
- PMID-15788704 — van der Lely et al., Ghrelin structure and function, Endocr Rev 2004
Related
Educational Note: Ghrelin is an endogenous hormone included in this vault for educational purposes. Understanding ghrelin physiology is essential for comprehending the mechanisms of GH secretagogue peptides used in clinical practice.
#peptide #gh-axis #endogenous #not-sold