Ghrelin

Also known as: Lenomorelin, Acyl ghrelin, Hunger hormone

Evidence: Clinical

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Overview

28-amino-acid stomach hormone and the endogenous GHS-R1a ligand; drives hunger, GH release and gastric motility in human infusion studies.

Ghrelin is a 28-amino acid peptide hormone produced primarily in the stomach. It is the endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Research demonstrates roles in appetite regulation, GH secretion, gastric motility, and energy homeostasis. Studied for applications in cachexia, gastroparesis, and growth hormone deficiency.

Benefits

Food intake +28% (human RCT crossover, n=9), GH release (human, dose-dependent), gastric emptying in idiopathic gastroparesis (human, n=6), LV function, exercise capacity and lean mass in chronic heart failure (human, n=10, open label)

Dosing reference

Research dose: ~1 mcg/kg IV bolus for GH release (about 70 mcg; Takaya 2000); 3.6 nmol/kg SC (about 12 mcg/kg, ~850 mcg) for appetite (Druce 2006); 2 mcg/kg IV 2x daily in heart failure (Nagaya 2004); no established research range
Range: 70 to 850 mcg, 1-2x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 2 mg, 5 mg

Only Ser3-octanoylated ghrelin activates GHS-R1a; des-acyl ghrelin is inactive at this receptor (Kojima 1999). Human studies used IV bolus or infusion; one RCT showed a single SC injection of 3.6 nmol/kg raised energy intake 27% (Druce 2006). Acyl ghrelin disappears from plasma in about 10 min (Akamizu 2004). An IV dose raised glucose and lowered insulin for about 2 h in healthy men (Broglio 2001).

Mechanism

Ghrelin is a 28 amino acid orexigenic peptide primarily produced by gastric oxyntic cells. Requires octanoylation (fatty acid attachment) at Ser3 by GOAT enzyme for biological activity. Binds to GHS-R1a (growth hormone secretagogue receptor type 1a), a GPCR that couples to Gq and G12/13. In hypothalamus, stimulates appetite through NPY/AgRP neurons while inhibiting POMC neurons. In pituitary, stimulates GH release synergistically with GHRH. Also regulates gastric motility, reward pathways, and glucose homeostasis. Levels rise pre-meal and fall post-prandially.

Evidence

Clinical: at least one published human trial or an approved drug

Identified as the endogenous GHS-R ligand; a 28-residue stomach peptide whose Ser3 octanoyl group is required for activity (Kojima et al., 1999)
IV 0.2-5 mcg/kg released GH dose-dependently (peak 107 ng/mL at 5 mcg/kg) and raised ACTH, cortisol and prolactin in 4 men (Takaya et al., 2000)
IV infusion increased buffet energy intake 28% in every subject in a randomized double-blind crossover, n=9 (Wren et al., 2001)
Acyl ghrelin half-life 9-13 min, total ghrelin 27-31 min after IV bolus; adverse effects transient (Akamizu et al., 2004)
3 weeks of 2 mcg/kg IV twice daily improved LV ejection fraction, peak VO2 and lean mass in 10 chronic heart failure patients (Nagaya et al., 2004)
Human-trial status: ghrelin itself is not approved anywhere; the ghrelin-receptor agonist anamorelin was approved in Japan (Adlumiz, 22 Jan 2021) for cancer cachexia after the ROMANA phase 3 trials, and is not FDA-approved

References

Side effects

In a placebo-controlled study of 1-5 mcg/kg IV, adverse effects were transient and no more frequent than placebo (Akamizu 2004). Documented acute effects in humans: increased hunger and food intake (Wren 2001), a rise in blood glucose with a fall in insulin lasting about 2 h (Broglio 2001), and rises in ACTH, cortisol and prolactin (Takaya 2000). Flushing, sweating and a mild drop in blood pressure are commonly reported (anecdotal).

Storage

Storage: Refrigerated (2-8°C)
Lyophilized: 24+ months at room temperature
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: 9-13 min acyl ghrelin, 27-31 min total ghrelin (human, IV bolus; Akamizu 2004)
Bioavailability: SC injection of 3.6 nmol/kg was active on energy intake (human; Druce 2006); no absolute bioavailability figure located
Molecular weight: 3370.9 Da
Sequence: GS[S(n-octanoyl)]FLSPEHQRVQQRKESKKPPAKLQPR