Mechanism of Action
GHS-R1a Receptor Signaling
Acylated ghrelin binds GHS-R1a (growth hormone secretagogue receptor 1a), a constitutively active Gq-coupled GPCR expressed in hypothalamic AgRP/NPY neurons, pituitary somatotrophs, vagal afferents, and reward pathways. Receptor activation stimulates phospholipase C, raises intracellular calcium, and activates AgRP/NPY neurons in the arcuate nucleus that project to the paraventricular nucleus to increase food intake. Ghrelin also inhibits POMC/CART anorexigenic neurons.
GH Release and Metabolic Effects
Pituitary GHS-R1a activation directly stimulates GH secretion, synergizing with GHRH. This is the basis for the development of peptide GH secretagogues (GHRP-6, ipamorelin) that mimic ghrelin's GH-releasing activity. Beyond GH, ghrelin promotes lipogenesis, inhibits lipolysis, increases fat mass, reduces insulin secretion, and promotes glucose uptake -- a distinct metabolic phenotype from what appetite stimulation alone would produce.
Research Summary
Appetite and Obesity
Well EstablishedIV ghrelin infusion in humans reliably increases caloric intake by 28-30% at meals taken during infusion. Ghrelin levels are paradoxically low in obesity (receptor saturation or chronic regulation). Post-bariatric surgery: ghrelin levels fall dramatically after sleeve gastrectomy (removing most X/A cells) but less so after Roux-en-Y, correlating with differential weight loss outcomes. Ghrelin antagonism and GOAT inhibition are active anti-obesity strategies.
Cachexia and Wasting
Active ResearchGhrelin analogs (anamorelin, macimorelin) approved or in trials for cancer cachexia and COPD-related weight loss. IV ghrelin improves lean mass, appetite, and functional status in patients with cardiac cachexia and ESRD. The orexigenic and anabolic (GH-mediated) mechanisms make ghrelin attractive for wasting conditions.
Cardiovascular Protection
Active ResearchGhrelin receptors on cardiomyocytes and endothelium mediate cardioprotective effects: reduced apoptosis, improved contractility, anti-inflammatory signaling. IV ghrelin improves left ventricular function, exercise capacity, and cardiac output in heart failure patients. Mechanisms include reduced sympathetic tone, improved endothelial function, and direct myocardial effects independent of GH.
Calculate your Ghrelin dose Vial strength, BAC water, exact syringe draw in IU. Free, no signup. Open Calc →
Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Appetite/food intake research | 1-5 mcg/kg IV bolus or 1-3 mcg/kg/hour infusion | Single session | Intravenous |
| GH secretion research | 1 mcg/kg IV bolus | Single dose; measure GH at 0, 15, 30, 60 min | Intravenous |
Acylated ghrelin is required for GHS-R1a activity. Unacylated (des-acyl) ghrelin has distinct non-GHS-R effects and may be cardioprotective via different receptor(s). Research-grade peptide only.
Interactions
Safety Profile
IV ghrelin in research doses is generally well tolerated. Mild flushing and transient hypotension at higher doses. Increased appetite and GH levels are the expected pharmacological effects. No significant adverse effects on cortisol, prolactin, or TSH. Long-term chronic exogenous ghrelin administration: theoretical concern for weight gain and fat accumulation with sustained use. Ghrelin analogs used clinically (anamorelin) have shown acceptable tolerability in cancer cachexia trials. No established therapeutic dose for human use outside clinical trials.
References
- [1]Kojima M, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-660.
- [2]Wren AM, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86(12):5992-5995.
- [3]Nagaya N, et al. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol. 2001;280(5):R1483-R1487.