When humans are hungry, the endocrine system signals the urge to eat through a complex network of signaling molecules. Several peripheral and central peptides maintain energy balance; however, a single peptide hormone, ghrelin, known as the primary peripheral "hunger hormone," works alongside specific neuropeptides in the brain to initiate eating.
Ghrelin, a peripheral signaling peptide
Ghrelin is a 28-amino-acid peptide produced predominantly by P/D1 cells in the lining of the human stomach and epsilon cells in the pancreas. It is the only known circulating peptide hormone that directly stimulates appetite.
In the fasting state, ghrelin levels spike immediately before anticipated meals and drop sharply after food intake. Ghrelin travels through the bloodstream and crosses the blood-brain barrier, binding to the growth hormone secretagogue receptor (GHS-R) in the hypothalamus.
For ghrelin to activate its receptor, it must undergo a specific post-translational modification called octanoylation, which adds an 8-carbon fatty acid chain to its Serine-3 residue.
The enzyme ghrelin O-acyltransferase (GOAT) catalyzes the octanoylation reaction. However, non-acylated ghrelin remains in circulation but is biologically inactive regarding hunger signaling.
Signaling by Ghrelin
Ghrelin signaling to the hypothalamus works in three ways:
(i) Penetration of the arcuate nucleus (ARC) via the bloodstream and possibly by active transport through the blood-brain barrier (BBB) in other areas.
(ii) Activation of GHS receptors on vagal afferents, the sensory nerve fibers of the vagus nerve, to send hunger signals to the nucleus of the tractus solitarius (NTS), which in turn communicates with the hypothalamus.
(iii) The hypothalamus itself appears to produce small amounts of ghrelin, directly activating neuropeptide Y / agouti-related peptide (NPY/AgRP) neurons and neurons in the lateral hypothalamic area (LHA).
| Inactive ghrelin without the fatty acid modification: GSSFLSPEHQRVQQRKESKKPPAKLQPR | Active, octanoylated ghrelin: GSS(C8:0)FLSPEHQRVQQRKESKKPPAKLQPR |
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Figure 1: Structural models of human ghrelin. In the active form, Ser3 is modified by a fatty acid, primarily n-octanoic acid.
Ghrelin cells are found mainly in the stomach and duodenum, but also in the jejunum, lungs, pancreatic islets, gonads, adrenal cortex, placenta, and kidney. Ghrelin is also produced locally in the brain. Additionally, research suggests that ghrelin may be produced in the myocardium and have an 'autocrine/ paracrine' like effect within the heart. Ghrelin cells are also present in oxyntic glands (20% of cells), pyloric glands, and the small intestines.
{Wang Y, Guo S, Zhuang Y, Yun Y, Xu P, He X, Guo J, Yin W, Xu HE, Xie X, Jiang Y. Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor. Nat Commun. 2021 Aug 20;12(1):5064. [PMC]}
The Hypothalamic ARC Circuit
The Hypothalamic Arcuate Nucleus (ARC) circuit monitors metabolic state and drives survival, sensing hunger, satiety, and energy expenditure. ARC integrates circulating hormones, such as leptin and ghrelin, and nutrients to maintain homeostasis.
Once ghrelin reaches the Arcuate Nucleus (ARC) of the hypothalamus, it activates an explicit population of orexigenic or appetite-stimulating neurons, triggering the release of two powerful central neurotransmitting peptides:
Neuropeptide Y (NPY)
NPY, a 36-amino-acid peptide, acts as one of the most potent feeding stimulants in the central nervous system. When injected into the hypothalamus of animal models, NPY causes immediate, robust feeding behavior by binding to Y1 and Y5 receptors, decreasing energy expenditure while driving a strong preference for carbohydrate intake.
| [1RON:] NMR SOLUTION STRUCTURE OF HUMAN NEUROPEPTIDE Y YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRYX | [7VGX] Neuropeptide Y Y1 Receptor (NPY1R) in Complex with G Protein and its endogeneous Peptide-Agonist Neuropeptide Y (NPY). |
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Figure 2: Structural models of neuropeptide Y and neuropeptide Y binding complex.
{Monks SA, Karagianis G, Howlett GJ, Norton RS. Solution structure of human neuropeptide Y. J Biomol NMR. 1996 Dec;8(4):379-90. [Pubmed]; Park C, Kim J, Ko SB, Choi YK, Jeong H, Woo H, Kang H, Bang I, Kim SA, Yoon TY, Seok C, Im W, Choi HJ. Structural basis of neuropeptide Y signaling through Y1 receptor. Nat Commun. 2022 Feb 14;13(1):853. Erratum in: Nat Commun. 2022 Feb 25;13(1):1126.}