Ghrelin
Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, Batterham RL, Benoit SC, +4 more
Molecular Metabolism (2015)
The 2015 multi-author Molecular Metabolism review that consolidated the ghrelin field — fifty co-authors spanning the major laboratories that built ghrelin pharmacology across two decades, covering the receptor, signaling, gastrointestinal and central effects, sleep-wake regulation, reward-seeking, and the pharmacological landscape of the secretagogue class.
This is the consolidating multi-author review of ghrelin and the ghrelin receptor (GHSR-1a) published in Molecular Metabolism in 2015 by Timo Müller, Rubén Nogueiras, and an unusually large international author group of approximately 50 investigators representing essentially every major laboratory that contributed to the ghrelin field across its first two decades. The review covers the breadth of ghrelin biology in 24 pages: hormone structure and post-translational processing (octanoylation at serine-3 by ghrelin O-acyltransferase / GOAT, the modification that is essential for GHSR-1a binding), receptor identity and signaling (GHSR-1a as a Gq-coupled class A GPCR with β-arrestin recruitment driving desensitization), tissue distribution, endogenous regulation of secretion (postprandial suppression, fasting elevation), and the physiological roles ghrelin has been assigned across the body of evidence: growth-hormone release, appetite stimulation, energy partitioning, gastrointestinal motility, gastric acid secretion, learning and memory, sleep-wake cycle modulation, reward-seeking behavior, taste sensation, glucose metabolism, and cardiovascular signaling.
The pharmacology section is the part most relevant to the peptide corpus. The review walks the growth-hormone-secretagogue drug class — small peptide and non-peptide molecules that engage GHSR-1a — across the foundational GHRP-6 design lineage from Bowers et al. 1984, the selective-pentapeptide design of ipamorelin and its clean GH-release profile, the broader hexapeptide class (GHRP-2, GHRP-6, hexarelin), and the non-peptide spiropiperidine MK-677 / ibutamoren with its ~24-hour functional half-life and orally bioavailable PK. The review touches on the receptor decoupling that distinguishes pulsatile-versus-tonic GHSR-1a activation (hexarelin and ipamorelin produce pulsatile signaling; MK-677 produces tonic activation), the tachyphylaxis and desensitization patterns at chronic dosing, and the CD36-mediated cardiac binding off-target identified for hexarelin in Bodart et al. 2002.
The review is the consolidated reference for cross-linking ghrelin biology from the Ipamorelin peptide page, the MK-677 page, the Hexarelin page, and the GHRP-2 page. The GHSR-1a section of the peptide receptor pharmacology atlas rests on the cloning paper (Howard et al. 1996) and the endogenous-ligand identification (Kojima et al. 1999), with this review as the synthesizing narrative across the intervening 16 years of pharmacology.
This is a comprehensive narrative review rather than a primary research paper or a systematic-review-with-meta-analysis, and carries the corresponding methodological limitations: selection of source literature is at author discretion rather than via pre-registered protocol, evidence-quality grading is implicit rather than explicit, and the review reflects the consensus reading of the field at time of writing rather than a quantitative synthesis of effect sizes. The 50-author breadth is a strength for field coverage but a weakness for editorial coherence — the review's individual sections vary in depth and emphasis depending on which sub-group of authors took the lead, and the consolidated narrative does not always resolve methodological tensions across the contributing groups' positions. The publication date (2015) means that the review does not cover developments in the late 2010s and 2020s — particularly the lorcaserin-and-bariatric-context obesity-pharmacology developments, the GLP-1-class disruption of the broader appetite-pharmacology landscape (which substantially reframed what a ghrelin-targeting drug needs to do to be clinically interesting), or the more recent characterization of biased agonism at GHSR-1a. The conflict-of-interest disclosures across the author group are extensive and reflect the deep industry-academic-collaboration history of the field. The review's framing of the secretagogue drug class is largely descriptive rather than skeptical — the methodological caveats around the existing clinical-evidence base for GH-secretagogue agents (predominantly Phase 2 or earlier, with short follow-up windows, sponsorship concentration, and replication-outside-Europe-and-Asia gaps) are not always foregrounded as explicitly as a clinically-evidence-focused reader would prefer. The review serves the purpose this entry assigns it: a consolidated reference for ghrelin and GHSR-1a pharmacology that the peptide pages cross-link to, not a definitive critical-appraisal source.
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