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Ghrelin and Des-Acyl Ghrelin Inhibit Isoproterenol-Induced Lipolysis via a Non-Type 1a GHS Receptor

Muccioli G, Tschöp M, Papotti M, et al.

European Journal of Pharmacology/2001

Background

The discovery of ghrelin in 1999 (Kojima et al., Nature) revealed that the GHS-R1a receptor — previously identified as the target for synthetic GHRPs including GHRP-2 — was actually the receptor for an endogenous acylated peptide hormone produced in the stomach.

This finding retroactively validated GHRP-2 as a ghrelin mimetic and established that the GH-releasing effects of synthetic GHRPs were due to activation of the same pathway ghrelin uses in normal physiology. This study characterized the receptor pharmacology of ghrelin vs. GHRP-2 vs. des-acyl ghrelin at GHS-R1a.

Key Findings

Receptor binding:

  • GHRP-2 and acylated ghrelin compete for the same binding site on GHS-R1a with comparable Ki values
  • Des-acyl ghrelin (the predominant circulating form) shows markedly reduced GHS-R1a affinity, yet retains some metabolic effects via alternative receptor(s)

GH secretion:

  • GHRP-2 and ghrelin produce equivalent dose-dependent GH release in anterior pituitary cell culture
  • The EC50 for GH release is comparable between GHRP-2 and ghrelin at GHS-R1a

Receptor distribution:

  • GHS-R1a expressed in: anterior pituitary, hypothalamus (arcuate, ventromedial nuclei), hippocampus, and peripheral tissues
  • Distribution explains GHRP-2’s central GH-releasing effects plus its neuroendocrine appetite/cortisol modulatory properties

Mechanistic Importance

PropertyGHRP-2Ghrelin
GHS-R1a affinityHighHigh
GH release (pituitary)PotentPotent
Oral bioavailabilityMinimalNone
SC stabilityHoursMinutes
Acylation requiredNoYes (for GHS-R1a)

Clinical Significance

Understanding that GHRP-2 mimics ghrelin at GHS-R1a has important implications:

  1. Appetite stimulation: Like ghrelin, GHRP-2 can stimulate appetite via hypothalamic GHS-R1a — a consideration for patients using it in caloric restriction contexts
  2. Physiological basis: GHRP-2’s GH-releasing activity mirrors the pulsatile GH secretion normally driven by endogenous ghrelin, supporting its use as a GH axis modulator
  3. Synthetic advantage: GHRP-2 lacks ghrelin’s N-octanoylation requirement and is more metabolically stable for clinical use

Limitations

  • In vitro and animal data; direct receptor binding data in humans are limited
  • The alternative ghrelin receptor(s) mediating des-acyl ghrelin effects are not fully characterized

Compounds Studied

Ghrp 2

Related Conditions

Hormone Optimization

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