Peptides that make us feel hungry

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.

{Huda MS, Wilding JP, Pinkney JH. Gut peptides and the regulation of appetite. Obesity Rev. 2006 May;7(2):163-82. [PubMed]}

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).

    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.

    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.}

Agouti-Related Peptide (AgRP)

Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. Neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus synthesize AgRP.

AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. AgRP is one of the most potent and long-lasting appetite stimulators. In humans, the AGRP gene encodes the agouti-related peptide.

AgRP is a 132-amino-acid neuropeptide that acts through a highly precise competitive mechanism, as an endogenous antagonist and inverse agonist at Melanocortin-4 Receptors (MC4R). Under normal conditions, alpha-melanocyte-stimulating hormone (α-MSH) binds to MC4R to signal satiety or fullness. When AgRP is released, it blocks α-MSH from binding to MC4R, signaling the body to seek food. Expression of the agouti signaling protein (ASIP) during hair growth produces the red/yellow pigment pheomelanin.

Figure 3: Structural models of AgRP.

{Bolin KA, Anderson DJ, Trulson JA, Thompson DA, Wilken J, Kent SB, Gantz I, Millhauser GL. NMR structure of a minimized human agouti related protein prepared by total chemical synthesis. FEBS Lett. 1999 May 21;451(2):125-31. https://pubmed.ncbi.nlm.nih.gov/10371151/); Millhauser GL, McNulty JC, Jackson PJ, Thompson DA, Barsh GS, Gantz I. Loops and links: structural insights into the remarkable function of the agouti-related protein. Ann N Y Acad Sci. 2003 Jun;994:27-35. Loops and Links: Structural Insights into the Remarkable Function of the Agouti-Related Protein}

Orexins

Orexins, also known as hypocretins, are a pair of excitatory neuropeptides, Orexin-A (OxA) and Orexin-B (OxB), also known as hypocretin-1 and hypocretin-2. Orexins regulate the sleep–wake cycle, homeostasis, and the reward system.

OxA and OxB signal through the two closely related receptors, orexin receptor type 1 and type 2 (OX1R and OX2R, respectively), expressed widely across the central nervous system.

Orexinergic neurons respond to a wide variety of neuronal signals, as they receive projections from the amygdala and cortex in response to stress, from the nucleus accumbens (NAc) and the ventral tegmental area (VTA) to regulate reward and motivation, and from the ventrolateral preoptic nucleus of the hypothalamus to regulate the sleep-wake cycle and circadian rhythms. A small population of neurons in the lateral hypothalamus produces orexins.

Orexins regulate wakefulness, energy homeostasis, and reward pathways. Orexins increase the craving for food and excite various brain nuclei to affect an organism's wakefulness by affecting their dopamine, norepinephrine, histamine, and acetylcholine systems.

Orexin-A

Orexin-A is a peptide composed of 33 amino acids, including an N-terminalpyroglutamyl residue and two intramolecular disulfide bridges between cysteine residues 6 and 12 and 7 and 14. Orexin A binds both OX1R and OX2R with close to equal affinity.

Orexin B

Orexin-B (also known as hypocretin-2) is an excitatory neuropeptide synthesized in the lateral hypothalamus that plays a critical role in regulating the sleep-wake cycle, feeding behavior, and energy homeostasis.

    Figure 4: Structural models of orexins. 

{Capó T, Lillo J, Rebassa JB, Badia P, Raïch I, Cubeles-Juberias E, Reyes-Resina I, Navarro G. The Orexin System in Addiction: Neuromodulatory Interactions and Therapeutic Potential. Brain Sci. 2025 Oct 14;15(10):1105. https://pmc.ncbi.nlm.nih.gov/articles/PMC12563207/; Hong C, Byrne NJ, Zamlynny B, Tummala S, Xiao L, Shipman JM, Partridge AT, Minnick C, Breslin MJ, Rudd MT, Stachel SJ, Rada VL, Kern JC, Armacost KA, Hollingsworth SA, O'Brien JA, Hall DL, McDonald TP, Strickland C, Brooun A, Soisson SM, Hollenstein K. Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation. Nat Commun. 2021 Feb 5;12(1):815. https://pmc.ncbi.nlm.nih.gov/articles/PMC7864924/; Takai T, Takaya T, Nakano M, Akutsu H, Nakagawa A, Aimoto S, Nagai K, Ikegami T. Orexin-A is composed of a highly conserved C-terminal and a specific, hydrophilic N-terminal region, revealing the structural basis of specific recognition by the orexin-1 receptor. J Pept Sci. 2006 Jul;12(7):443-54. https://pubmed.ncbi.nlm.nih.gov/16429482/; Xia L, Liu HY, Wang BY, Lin HN, Wang MC, Ren JX. A review of physiological functions of orexin: From instinctive responses to subjective cognition. Medicine (Baltimore). 2023 Jun 30;102(26):e34206. https://pmc.ncbi.nlm.nih.gov/articles/PMC10313292/}