Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin.
This review synthesizes current scientific understanding of ghrelin, a hormone originally characterized primarily for its role in appetite stimulation and growth hormone release. The authors trace the full arc of ghrelin biology: from its biosynthesis (preproghrelin processing and O-acylation by the enzyme GOAT to produce the active acyl-ghrelin form), through its receptor pharmacology at GHSR1a, to its wide-ranging physiological roles. The review highlights that des-acyl ghrelin—the predominant circulating form—can exert effects independently of or with lower potency at GHSR1a, and that truncated "mini-ghrelins" may act as competitive antagonists. Recent cryo-EM structural data on GHSR1a are discussed as a framework for understanding biased signaling and drug design. The authors also review ghrelin's roles in glucose regulation, gastric function, cardiovascular tone, bone remodeling, renal hemodynamics, innate immunity, and the central nervous system—including links to neuroprotection, depression, Alzheimer's disease, and addiction. Translational topics covered include ghrelin stabilization strategies, synthetic ligands (agonists, antagonists, inverse agonists), LEAP-2-based approaches, and GOAT inhibitors. As a narrative review, the paper does not generate new experimental data, so primary evidence quality depends on the underlying cited studies.
Why this grade: This is a narrative review article that synthesizes existing literature rather than presenting original experimental or clinical trial data, so it is graded as review-level evidence.
Our understanding of Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from considering it to be a "hunger hormone" to a pleiotropic regulator of whole-body physiology. This review synthesizes the current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, a high-potency GHSR1a agonist; des-acyl ghrelin predominates in circulation and exerts context-dependent, GHSR1a-independent, or low-potency effects, while truncated "mini-ghrelins" can act as competitive antagonists. The emergence of synthetic ligands, agonists, antagonists, and reverse-agonists has provided the necessary tools to decipher GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and provide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond the regulation of feeding and growth-hormone release, ghrelin modulates glucose homeostasis, gastric secretion and motility, cardiovascular tone, bone remodeling, renal hemodynamics, and innate immunity. Ghrelin broadly dampens pro-inflammatory responses and promotes reparative macrophage phenotypes. In the emerging scholarship on ghrelin's activity in the central nervous system, ghrelin has been found to influence neuroprotection, stress reactivity, and sleep architecture, and has also been implicated in depression, Alzheimer's disease, and substance-abuse disorders. Practical and transitional aspects are also highlighted in the literature: approaches for ghrelin stabilization; recent GHSR1a agonists/antagonists and inverse agonists findings; LEAP-2-based strategies; and emerging GOAT inhibitors. Together, structural insights and pathway selectivity position the ghrelin system as a druggable axis for the management of inflammatory diseases, neuropsychiatric and addiction conditions, and for obesity treatment in the post-GLP-1 receptor agonist era.
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