Acylation, a Conductor of Ghrelin Function in Brain Health and Disease
Open accessAbstract
Acyl-ghrelin (AG) is an orexigenic hormone that has a unique octanoyl modification on its third serine residue. It is often referred to as the “hunger hormone” due to its involvement in stimulating food intake and regulating energy homeostasis. The discovery of the enzyme ghrelin-O-acyltransferase (GOAT), which catalyses ghrelin acylation, provided further insights into the relevance of this lipidation process for the activation of the growth hormone secretagogue receptor (GHS-R) by acyl-ghrelin. Although acyl-ghrelin is predominantly linked with octanoic acid, a range of saturated fatty acids can also bind to ghrelin possibly leading to specific functions. Sources of ghrelin acylation include beta-oxidation of longer chain fatty acids, with contributions from fatty acid synthesis, the diet, and the microbiome. In addition, both acyl-ghrelin and unacyl-ghrelin (UAG) have feedback effects on lipid metabolism which in turn modulate their levels. Recently we showed that whilst acyl-ghrelin promotes adult hippocampal neurogenesis and enhances memory function, UAG inhibits these processes. As a result, we postulated that the circulating acyl-ghrelin:unacyl-ghrelin (AG:UAG) ratio might be an important regulator of neurogenesis and cognition. In this review, we discuss emerging evidence behind the relevance of ghrelin acylation in the context of brain physiology and pathology, as well as the current challenges of identifying the provenance of the acyl moiety.
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Ghrelin is a neuroprotective hormone secreted by cells in the stomach.
“Ghrelin, a neuroprotective hormone secreted by cells in the stomach, plays a key role in regulating the appetite and energy balance of the body [20, 29, 44].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [20]
The Introduction describes ghrelin as a stomach peptide that stimulates hunger during low energy balance. It attributes beneficial effects in neurodegenerative disorders to acyl-ghrelin specifically, while reporting that unacylated ghrelin impairs neurogenesis and memory. Calling ghrelin generally neuroprotective therefore omits a distinction central to this review. (LLM, conf=0.84)
Experimental — accuracy not yet measuredElevated ghrelin levels exert anti-inflammatory effects, metabolic regulation, and promote cognitive enhancement.
“This is an interesting finding, as elevated ghrelin levels are known to exert anti-inflammatory effects, metabolic regulation, and promote cognitive enhancement [20, 45, 47].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [20]
The Abstract (page unavailable) says acyl-ghrelin regulates energy homeostasis and enhances memory function, supporting the metabolic and cognitive parts of the claim. It distinguishes acyl-ghrelin from unacylated ghrelin, which it says inhibits memory-related processes. The passages found for “anti-inflammatory effects” and “inflammation” do not establish an anti-inflammatory effect, so the claim is not fully supported. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGhrelin enhances synaptic plasticity.
“It binds to growth hormone secretagogue receptor (GHSR), and it has been shown to protect neurons from β-amyloid-induced toxicity, reduce tau phosphorylation, and enhance synaptic plasticity [20, 44–46].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [20]
The Introduction (page unavailable) says ghrelin regulates brain plasticity, and the Abstract (page unavailable) says acyl-ghrelin promotes hippocampal neurogenesis and enhances memory. Those passages support a positive role in brain plasticity, but they do not specifically state that ghrelin enhances synaptic plasticity. (LLM, conf=0.76)
Experimental — accuracy not yet measuredGhrelin plays a key role in regulating appetite and energy balance.
“Ghrelin, a neuroprotective hormone secreted by cells in the stomach, plays a key role in regulating the appetite and energy balance of the body [20, 29, 44].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [20]
Ghrelin binds to growth hormone secretagogue receptor (GHSR).
“It binds to growth hormone secretagogue receptor (GHSR), and it has been shown to protect neurons from β-amyloid-induced toxicity, reduce tau phosphorylation, and enhance synaptic plasticity [20, 44–46].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [20]
Ghrelin protects neurons from β-amyloid-induced toxicity.
“It binds to growth hormone secretagogue receptor (GHSR), and it has been shown to protect neurons from β-amyloid-induced toxicity, reduce tau phosphorylation, and enhance synaptic plasticity [20, 44–46].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [20]
The Introduction discusses acyl-ghrelin’s effects on neurogenesis and memory, and the section on ghrelin acylation discusses dementia, but neither reports protection from β-amyloid-induced neuronal toxicity. Searches for β-amyloid, amyloid-beta-induced neuronal death, and Aβ toxicity found no passage addressing that specific claim. (LLM, conf=0.72)
Experimental — accuracy not yet measuredGhrelin reduces tau phosphorylation.
“It binds to growth hormone secretagogue receptor (GHSR), and it has been shown to protect neurons from β-amyloid-induced toxicity, reduce tau phosphorylation, and enhance synaptic plasticity [20, 44–46].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [20]
The Introduction (page unavailable) describes acyl-ghrelin’s effects on neurogenesis and memory, and the acylation section discusses its association with dementia. Neither addresses tau phosphorylation. Searches for “tau phosphorylation” and “tau protein hyperphosphorylation” found no passage in our copy saying that ghrelin reduces it. (LLM, conf=0.72)
Experimental — accuracy not yet measured
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“As relevant to this review, MCFA such as octanoic acid used for ghrelin acylation, as well as SCFA, are water-soluble and may enter cells and organelles through unselective membrane pores (Papamandjaris et al., 1998; Antonenkov and Hiltunen, 2012).”
BackgroundFatty Acid Transport and Utilization for the Developing Brain
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“However, incubation of these with butyric acid (C4: 0) or valeric acid (C5:0) did not affect ghrelin secretion (Lu et al., 2012).”
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“Indeed, using a fluorescent form of C12:0, UAG increased the uptake of this fatty acid into cardiomyocytes (Lear et al., 2010).”
BackgroundThe expression of ghrelin O-acyltransferase (GOAT) in human tissues.
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Sensing of Fatty Acids for Octanoylation of Ghrelin Involves a Gustatory G-Protein
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Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode
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Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor
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Architectural Organization of the Metabolic Regulatory Enzyme Ghrelin O-Acyltransferase*
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On the mechanism of oleate transport across human brain microvessel endothelial cells
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Acyltransferases for secreted signalling proteins (Review)
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Uncoupling protein-2 decreases the lipogenic actions of ghrelin.
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“Acyl-ghrelin mediates the beneficial effects associated with calorie restriction (CR) in neurodegenerative disorders, including Parkinson’s Disease (PD) (Andrews et al., 2010).”
BackgroundBarazzoni, R., Cappellari, G. G., Palus, S., Vinci, P., Ruozi, G., Zanetti, M., Semolic, A., Ebner, N., von Haehling, S., Sinagra, G., et al. (2017) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12254 · Cited by 44 · cited 1× · see citing works
“Whilst intravenous infusion of LCFA increased both acyl-ghrelin and the AG: TG ratio in rats (Barazzoni et al., 2017).”
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“These amino acids were later characterized and the N-terminal binding motif of acyl-ghrelin was confirmed to substantially contribute to the binding energy of the peptide-receptor complex and ghrelin proposed to assume a rigid helical conformation involving C-terminal residues (Bender et al., 2019).”
BackgroundMethodMembrane bound O-acyltransferases and their inhibitors.
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“However, it contains two highly conserved residues: asparagine (Asn307)—which seems to be essential for the interactions with the substrates, and histidine (His338)—thought to be involved in the catalytic mechanism (Taylor et al., 2013; Masumoto et al., 2015).”
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“Acyl-ghrelin detected in gastric cells correlated with the dose of dietary tioctanoin, which supports the theory of direct absorption of the fatty acyl substrate for ghrelin acylation via the gut (Lemarié et al., 2015).”
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Ghrelin stimulates fatty acid oxidation and inhibits lipolysis in isolated muscle from male rats
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“Furthermore, neither acylated nor UAG altered the incorporation of fatty acids into TAGs or phospholipids (Kraft et al., 2019).”
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“, 2005) and plasma, liver and stomach of suckling rats (Lemarié et al., 2016).”
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“Consistent with these studies, LCFA was needed for the acylation of ghrelin in a ghrelinoma cell line (MGN3-1) (Bando et al., 2016).”
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Pregnancy, but not dietary octanoic acid supplementation, stimulates the ghrelin-pituitary growth.
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Inhibitory Effect of Oleic Acid on Octanoylated Ghrelin Production.
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Metabolic control of adult neural stem cell behavior
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Understanding peptide hormones: from precursor proteins to bioactive molecules
Voilquin, L., Wiggenhorn, A. L., & Svensson, K. J. (2025) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2025.03.014 · Cited by 18 · see citing works
The Pathologic Roles and Therapeutic Implications of Ghrelin/GHSR System in Mental Disorders
Mao, Q., Wang, J., Yang, Z., Ding, R., Lv, S.-Y., & Ji, X.-Y. (2024) · Depression and Anxiety · doi:10.1155/2024/5537319 · Cited by 10 · see citing works
“In addition, in terms of neurogenesis, des-acyl ghrelin and acyl-ghrelin may play opposite roles, and changes in their ratios may be associated with certain neurodegenerative diseases [12, 13].”
A hub for regulation of mitochondrial metabolism: Fatty acid and lipoic acid biosynthesis
Dieckmann, C. (2023) · IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology · doi:10.1002/iub.2802 · Cited by 10 · see citing works
Ezaki, O. (2024) · Nutrients · doi:10.3390/nu16162606 · Cited by 7 · see citing works
“Ghrelin O-acyltransferase (GOAT) acylates proghrelin with C8:0 to produce acyl-proghrelin, which is converted to acyl-ghrelin by the prohormone convertase [22,24].”
BackgroundGhrelin’s role in sleep and sleep deprivation: a narrative review
Ditmer, M., Wojtera, A., Gabryelska, A., Turkiewicz, S., Białasiewicz, P., Strzelecki, D., & Sochal, M. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1744781 · Cited by 6 · see citing works
Investigating ghrelin and its isoforms in eating disorders: a network meta-analysis.
Dani, C., Giachetti, S., Mura, M., Tedesco, S., Rossi, E., Cassioli, E., Tarchi, L., Micali, N., Ricca, V., & Castellini, G. (2025) · Progress in Neuro-psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111489 · Cited by 5 · see citing works
Kanda, T., & Urai, H. (2026) · Nutrients · doi:10.3390/nu18071095 · Cited by 4 · see citing works
“This modification depends on the availability of medium-chain FAs, particularly octanoic acid, which serves as an essential acyl donor [19].”
Futran-Sheinberg, E. J., Urbina, V., Nava, S., Sanchez, D., Guzmán-Valdivia, G., & Zetter, M. A. (2025) · Neuroglia · doi:10.3390/neuroglia6030035 · Cited by 4 · see citing works
“This contrasts with acylated ghrelin, which acts through GHSR1 α and is ineffective in cells lacking this receptor, such as N9 microglia [131].”
de Soysa, A. K. D., Langaas, M., Grill, V., Martins, C., & Mostad, I. L. (2025) · PLoS ONE · doi:10.1371/journal.pone.0312815 · Cited by 3 · see citing works
Luo, Y., Long, Y., Lu, X., & Cui, Z.-B. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27062875 · Cited by 2 · see citing works
“…that L-carnosine promotes mitochondrial β -oxidation of fatty acids by up-regulating or down-regulating genes involved in this catabolic process [36,37], thus promoting the liver’s capacity to break down excess fatty acids and reducing their conversion into triglycerides and the formation of lipid…”
Li, X., Ji, Q., Zhong, C., Wu, C., Wu, J., Yuan, C., & Ran, J.-M. (2024) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2024.149844 · Cited by 2
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“This is an interesting finding, as elevated ghrelin levels are known to exert anti-inflammatory effects, metabolic regulation, and promote cognitive enhancement [20, 45, 47].”
InfluentialBukhari, S. M. S., Shah, M., Ali, R., Rehman, N. U., Ahmad, P., & Shah, F. (2026) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2026.117809 · Cited by 1 · see citing works
Detection of natural autoimmunity to ghrelin in diabetes mellitus
Kasim, R. H., Chillon, T., Eleftheriadou, A., Rijntjes, E., Minich, W., Zechmann, S., & Schomburg, L. (2024) · Frontiers in Medical Technology · doi:10.3389/fmedt.2024.1407409 · Cited by 1 · see citing works
“The analysis of aAb to endocrine signals, receptors or transporters constitutes a speci fi c challenge, as these biomolecules usually undergo intensive posttranslational modi fi cations, including proteolytic processing, glycation or even acylation as in case of ghrelin (24).”
BackgroundHow lipid ingestion is sensed: the mechanisms underlying intestinal hormone secretion
Santos-Hernández, M., Gribble, F., & Reimann, F. (2026) · Clinical science · doi:10.1042/cs20250793
Peptide Hormones in Appetite Regulation: A Complex Network
Abdollahi, S., Adam, H., & Musaimi, O. A. (2026) · Pharmaceuticals · doi:10.3390/ph19070989
“Biological activity requires acylation by the enzyme ghrelin O-acyltransferase (GOAT), enabling ghrelin to cross the blood–brain barrier (BBB) and bind to growth hormone secretagogue receptors (GHSR) on NPY/AgRP neurons [37–39].”
Lis, M., Miłuch, T., Krupa, R., Langowska, A., & Majdowski, M. (2026) · Scientific Reports · doi:10.1038/s41598-026-54095-x
Meal timing and ghrelin: A chrononutritional perspective on weight regulation potential
Khaira, F., & Sulastri, D. (2026) · Chronobiology International · doi:10.1080/07420528.2026.2624753
“The biosynthesis of ghrelin begins with the translation of preproghrelin, which is processed into proghre-lin and subsequently acylated at the third serine residue with an octanoic or decanoic fatty acid (Abdalla 2015; Thomas et al. 2022).”
Nakagawa, M., Kanai, S., Kayashita, A., & Kayashita, J. (2025) · Cureus · doi:10.7759/cureus.99590
“Although the MCT powder used in this study did not specify its MCFA content, most commercially available MCTs consist primarily of C8:0 and C10:0 [23].”
The protective PLCG2 variants delay Alzheimer's disease onset age in APOE ϵ4 carriersPreprint
Jeskanen, H., Heikkinen, S., Kervinen, I., Lehtisalo, J., Ngandu, T., Willman, R.-M., Rosa, J., Hoffmann, D., FinnGen, Leinonen, V., et al. (2025) · medRxiv · doi:10.1101/2025.09.22.25336304
“Ghrelin, a neuroprotective hormone secreted by cells in the stomach, plays a key role in regulating the appetite and energy balance of the body (24,40,41).”
- Authors
- Thomas, A. S., Sassi, M., Angelini, R., Morgan, A. H., & Davies, J. S.
- Affiliations
- Swansea University (GB)
- Corresponding author
- Davies, Jeffrey S.
- Venue
- Frontiers in Physiology
- Publisher
- Frontiers Media SA
- Published
- 2022-06-30
- Volume
- 13
- Pages
- 831641-831641
- ISSN
- 1664-042X (ISSN-L)
- PMC
- PMC9280358
- OpenAlex
- W4283757610
- Cited by
- 17
- References
- 158
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 4 · 2023: 1
- FWCI
- 0.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Physiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Engineering and Physical Sciences Research Council
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- ghrelin, acylation, ghrelin O-acyltransferase, growth hormone secretagogue receptor, fatty acid beta-oxidation, gut microbiota, lipid metabolism, hippocampal neurogenesis, memory, energy homeostasis, dietary intake
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