PeptideJournal
Reference15 min read

Endogenous Peptides: Your Body's Natural Peptides

Your body runs on peptides. Right now, as you read this, hundreds of distinct peptide molecules are circulating through your bloodstream, firing across synapses in your brain, patrolling your skin for bacteria, and shuttling signals between your mitochondria and your cell nuclei.

Your body runs on peptides. Right now, as you read this, hundreds of distinct peptide molecules are circulating through your bloodstream, firing across synapses in your brain, patrolling your skin for bacteria, and shuttling signals between your mitochondria and your cell nuclei. These are endogenous peptides — molecules your body manufactures on its own, without any external supplementation.

The word "endogenous" comes from the Greek endo (within) and genes (born). Endogenous peptides are born within you, encoded in your DNA and assembled by your cells to run the biological programs that keep you alive. This guide catalogs the major families, explains how your body produces them, and maps what they regulate.

Table of Contents

What Makes a Peptide Endogenous

An endogenous peptide is any amino acid chain shorter than roughly 100 residues that is naturally produced by your cells or tissues. This distinguishes them from synthetic peptides (made in laboratories) and exogenous peptides (introduced from food, supplements, or drugs).

The distinction matters because endogenous peptides are integrated into your body's regulatory systems through millions of years of evolution. They fit precisely into specific receptors. They are produced in regulated amounts at regulated times. And when their levels shift — through aging, disease, or stress — measurable physiological consequences follow.

To understand the basics of peptide structure and how amino acids link together, see our guide on amino acids, peptide bonds, and biochemistry basics.

How Your Body Produces Peptides

Almost all endogenous peptides start as larger precursor proteins called pre-pro-peptides. The production pathway follows a consistent pattern:

  1. Gene transcription: A gene in nuclear DNA (or, in the case of mitochondrial-derived peptides, mitochondrial DNA) is transcribed into messenger RNA.

  2. Translation: Ribosomes in the endoplasmic reticulum translate the mRNA into a large, inactive precursor protein. This precursor contains a signal sequence, pro-regions, and one or more embedded peptide sequences.

  3. Signal peptide removal: The signal sequence directs the precursor into the secretory pathway, then gets clipped off.

  4. Proteolytic processing: Specific enzymes called prohormone convertases (PC1/3 and PC2 are the major ones) cut the precursor at defined sites, releasing individual peptide fragments.

  5. Post-translational modifications: The liberated peptides may be amidated, acetylated, phosphorylated, sulfated, or cyclized to reach their final active form.

  6. Packaging and storage: Active peptides are packaged into secretory vesicles (large dense-core vesicles in neurons, secretory granules in endocrine cells) and stored until a signal triggers their release.

One precursor can yield multiple different peptides. Pro-opiomelanocortin (POMC), for example, is a single precursor protein that gives rise to ACTH, beta-endorphin, alpha-MSH, and several other bioactive peptides. Which peptides are released depends on which convertase enzymes are present in each tissue — the pituitary processes POMC differently from the hypothalamus.

This means the same gene can produce different peptide products in different tissues, a concept called tissue-specific processing.

Peptide Hormones: The Endocrine Messengers

Peptide hormones are secreted into the bloodstream by endocrine glands and travel to distant target tissues. They cannot cross cell membranes (they are too large and hydrophilic), so they bind to receptors on the cell surface — predominantly G protein-coupled receptors (GPCRs) — and trigger intracellular signaling cascades through second messengers like cAMP, IP3, and calcium ions.

Metabolic Hormones

Insulin (51 amino acids, two disulfide-linked chains) is produced by pancreatic beta cells and is the body's primary anabolic hormone. It drives glucose uptake into muscle and fat cells, promotes glycogen synthesis, and inhibits gluconeogenesis. Insulin's discovery in 1921 by Banting and Best remains one of medicine's greatest breakthroughs.

Glucagon (29 amino acids) is insulin's metabolic counterpart, produced by pancreatic alpha cells. It raises blood glucose by stimulating glycogenolysis and gluconeogenesis in the liver. For a full profile, see our glucagon guide.

Amylin (37 amino acids) is co-secreted with insulin from beta cells. It slows gastric emptying, suppresses glucagon secretion, and promotes satiety. Pramlintide (Symlin) is a synthetic amylin analog used in diabetes management. Read more in our amylin profile.

GLP-1 (glucagon-like peptide-1, 30 amino acids) is released by intestinal L-cells after meals. It stimulates insulin secretion, slows gastric emptying, and suppresses appetite. GLP-1's natural half-life is only about 2 minutes because the enzyme DPP-4 rapidly degrades it. Drugs like semaglutide and tirzepatide are engineered analogs that resist DPP-4 and last days instead of minutes.

GIP (glucose-dependent insulinotropic polypeptide, 42 amino acids) is the other major incretin hormone, released by intestinal K-cells. Tirzepatide is a dual GIP/GLP-1 agonist — the first drug to target both incretin receptors simultaneously.

Growth and Reproductive Hormones

Growth hormone-releasing hormone (GHRH) is a 44-amino-acid peptide from the hypothalamus that stimulates growth hormone secretion. CJC-1295 is a synthetic GHRH analog with an extended half-life.

Ghrelin (28 amino acids) is the "hunger hormone," produced primarily by stomach cells. It stimulates appetite, promotes growth hormone release, and rises before meals. It is the only known circulating hormone that increases food intake.

Gonadotropin-releasing hormone (GnRH) (10 amino acids) is the master switch for reproductive function. Pulsatile GnRH release from the hypothalamus controls LH and FSH secretion from the pituitary, which in turn drives gonadal function.

Oxytocin (9 amino acids) is produced in the hypothalamus and released from the posterior pituitary. It triggers uterine contractions during labor and milk ejection during breastfeeding, and modulates social bonding and trust. See our oxytocin guide.

Vasopressin (ADH) (9 amino acids) is oxytocin's structural twin — the two differ at only two of nine positions. But their functions diverge sharply: vasopressin regulates water retention in the kidneys and constricts blood vessels.

Fluid and Mineral Balance

Atrial natriuretic peptide (ANP) (28 amino acids) is released by heart atrial cells when blood volume increases. It promotes sodium and water excretion, lowering blood pressure. B-type natriuretic peptide (BNP, 32 amino acids) from the ventricles does something similar. BNP blood levels are used clinically to diagnose heart failure.

Parathyroid hormone (PTH) (84 amino acids) regulates calcium homeostasis by stimulating bone resorption, kidney calcium reabsorption, and vitamin D activation.

Calcitonin (32 amino acids) from thyroid C-cells opposes PTH by inhibiting bone resorption and lowering blood calcium.

Neuropeptides: The Brain's Chemical Vocabulary

The human genome encodes roughly 90 neuropeptide precursor genes, which are processed into about 100 bioactive neuropeptides (NCBI NBK28247). Neuropeptides differ from classical neurotransmitters in several fundamental ways:

  • They are synthesized in the cell body, not at the synapse
  • They are packaged into large dense-core vesicles rather than small synaptic vesicles
  • They require higher-frequency stimulation for release
  • They often act through volume transmission — diffusing over longer distances rather than crossing a single synaptic cleft
  • They typically bind to GPCRs rather than ligand-gated ion channels

Neuropeptide signaling is ancient. Genome sequencing reveals neuropeptide genes in cnidarians (jellyfish, corals) and ctenophores (comb jellies) — organisms where all neural signaling is peptide-based, predating the evolution of amine neurotransmitters like dopamine and serotonin.

Opioid Peptides

Your body produces its own painkillers. The endogenous opioid system includes three main families:

Beta-endorphin (31 amino acids) is released from the pituitary and acts on mu-opioid receptors. It is 18 to 33 times more potent than morphine as an analgesic. Beta-endorphin levels rise during exercise (contributing to "runner's high"), during laughter, and during social bonding.

Enkephalins — met-enkephalin and leu-enkephalin (both 5 amino acids) — are the smallest opioid peptides. They act primarily on delta-opioid receptors and modulate pain in the spinal cord and brainstem.

Dynorphins (13-17 amino acids) preferentially bind kappa-opioid receptors and are involved in stress responses, mood regulation, and the experience of dysphoria.

Appetite and Energy Peptides

Neuropeptide Y (NPY) (36 amino acids) is one of the most abundant neuropeptides in the brain and a potent stimulator of food intake. Its release in the hypothalamus precedes feeding onset and shifts energy balance toward storage.

Agouti-related peptide (AgRP) (132 amino acids in precursor form) works alongside NPY to promote hunger and is a natural antagonist of melanocortin receptors.

Alpha-MSH (13 amino acids) opposes NPY/AgRP by activating melanocortin-4 receptors to suppress appetite. Mutations in the MC4R gene are the most common genetic cause of severe obesity.

Orexins/hypocretins (33 and 28 amino acids) regulate wakefulness and appetite. Loss of orexin-producing neurons causes narcolepsy. Suvorexant (Belsomra) is a dual orexin receptor antagonist used as a sleep aid.

Mood and Social Behavior Peptides

Oxytocin and vasopressin, discussed above as hormones, also function as neuropeptides within the brain, modulating social behavior, pair bonding, and stress reactivity.

Selank is based on the endogenous peptide tuftsin, a natural immunomodulatory tetrapeptide. Selank (a synthetic hexapeptide analog) has been studied for anxiolytic effects.

Cholecystokinin (CCK) acts as both a gut hormone (promoting digestion) and a brain neuropeptide (modulating anxiety and satiety).

Pain and Inflammation Peptides

Substance P (11 amino acids) is the prototypical pain-signaling neuropeptide. It binds to the NK1 receptor and transmits pain signals from peripheral nerves to the spinal cord. It also promotes neurogenic inflammation by causing vasodilation and plasma leakage.

Calcitonin gene-related peptide (CGRP) (37 amino acids) is a potent vasodilator released from sensory neurons. CGRP plays a central role in migraine headaches, and anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab) have become a major advance in migraine prevention.

Bradykinin (9 amino acids) is generated in plasma during tissue injury and inflammation. It dilates blood vessels, increases permeability, and stimulates pain receptors.

Antimicrobial Peptides: Your Innate Immune Arsenal

Long before your adaptive immune system generates specific antibodies, your innate immune system deploys antimicrobial peptides (AMPs) that kill pathogens on contact. Humans produce two major AMP families.

Defensins

Defensins are small (29-45 amino acids), cysteine-rich peptides with three intramolecular disulfide bonds. They punch holes in bacterial membranes, and their spectrum extends to gram-positive bacteria, gram-negative bacteria, fungi, and some viruses.

Human defensins come in two subfamilies:

  • Alpha-defensins: Found in neutrophil granules (HNP-1 through HNP-4) and in Paneth cells of the small intestine (HD-5, HD-6). A single neutrophil carries roughly 5% of its total protein as defensins.
  • Beta-defensins: Produced by epithelial cells in the skin, airways, and urogenital tract. hBD-1 is expressed constitutively. hBD-2 and hBD-3 are induced by infection and inflammation.

For a comprehensive guide, see our defensins overview.

Cathelicidins

LL-37 is the only cathelicidin in humans — a 37-amino-acid peptide released from its precursor (hCAP-18) by proteinase 3. It is found in neutrophils, monocytes, mast cells, and epithelial cells.

LL-37 goes well beyond direct bacterial killing. It recruits immune cells to infection sites, promotes wound healing, stimulates angiogenesis, and modulates inflammatory responses. Its expression is regulated by vitamin D — one mechanism by which vitamin D supports immune function.

Dysregulated LL-37 is implicated in skin diseases: too little LL-37 contributes to the infection susceptibility seen in atopic dermatitis, while overproduction or abnormal processing is linked to psoriasis and rosacea.

For a full research overview, see our LL-37 profile.

Mitochondrial-Derived Peptides: A Newly Discovered Family

Until 2001, scientists assumed that mitochondrial DNA encoded only 13 proteins (all subunits of the electron transport chain), 22 tRNAs, and 2 rRNAs. Then researchers discovered that short open reading frames hidden within mitochondrial ribosomal RNA genes actually encode small bioactive peptides.

Eight mitochondrial-derived peptides (MDPs) have been identified so far:

Humanin (24 amino acids, discovered 2001) was found during a search for neuroprotective factors in Alzheimer's disease. It protects against amyloid-beta toxicity, improves insulin sensitivity, and reduces apoptosis. For more, see our humanin profile.

MOTS-c (16 amino acids, discovered 2015) is encoded within the 12S ribosomal RNA gene. Under metabolic stress or exercise, MOTS-c translocates from mitochondria to the cell nucleus, where it regulates the expression of genes with antioxidant response elements. Circulating MOTS-c levels rise roughly 1.6-fold during exercise in humans. Its levels decline with age — 70-to-81-year-olds have about 21% less circulating MOTS-c than 18-to-30-year-olds.

SHLP 1-6 (small humanin-like peptides) are encoded within the 16S ribosomal RNA gene alongside humanin. SHLP2 in particular shows insulin-sensitizing and cytoprotective effects similar to humanin.

MDPs represent a form of retrograde signaling — communication from mitochondria back to the nucleus. They have been called "mitokines" or "mitochondrial hormones" because they circulate in the blood and act on distant tissues, blurring the line between organelle and endocrine gland.

Gastrointestinal Peptides: The Gut's Signaling Network

Your gastrointestinal tract is the largest endocrine organ in the body, producing dozens of peptide hormones that coordinate digestion, appetite, and metabolism.

Gastrin (17 or 34 amino acids) stimulates hydrochloric acid secretion from parietal cells of the stomach. Excess gastrin production (as in Zollinger-Ellison syndrome from gastrinomas) causes severe peptic ulcers.

Secretin (27 amino acids) was the first hormone ever identified (by Bayliss and Starling in 1902). It stimulates bicarbonate secretion from the pancreas to neutralize acidic chyme entering the duodenum.

Cholecystokinin (CCK) (8-58 amino acids in various forms) triggers gallbladder contraction, pancreatic enzyme secretion, and satiety signaling to the brain.

GLP-1 and GIP (discussed above) act as incretins — hormones released after eating that amplify insulin secretion in a glucose-dependent manner.

Peptide YY (PYY) (36 amino acids) is released by intestinal L-cells after meals and suppresses appetite through the "ileal brake" mechanism.

Motilin (22 amino acids) triggers the migrating motor complex — the housekeeping contractions that sweep undigested material through the intestines between meals. Erythromycin, the antibiotic, happens to be a motilin receptor agonist, which explains its side effect of stimulating gut motility.

Ghrelin from the stomach was mentioned above. It is the only gut peptide that stimulates rather than suppresses appetite.

Cardiovascular Peptides

Angiotensin II (8 amino acids) is generated from angiotensinogen by sequential cleavage by renin and angiotensin-converting enzyme (ACE). It constricts blood vessels, stimulates aldosterone release, and promotes sodium retention. ACE inhibitors (lisinopril, enalapril) and angiotensin receptor blockers (losartan, valsartan) — two of the most prescribed drug classes worldwide — work by blocking this peptide's effects.

Endothelin-1 (21 amino acids) is the most potent endogenous vasoconstrictor known. It is produced by vascular endothelial cells and plays roles in both normal vascular tone and in diseases like pulmonary hypertension.

Atrial and B-type natriuretic peptides (ANP, BNP) oppose the renin-angiotensin system by promoting sodium excretion and vasodilation.

Adrenomedullin (52 amino acids) is a vasodilatory peptide that also has antimicrobial properties. It is elevated in sepsis and heart failure.

How Endogenous Peptides Change With Age

Endogenous peptide levels do not remain constant across a lifetime. Several well-documented shifts occur:

  • Growth hormone and GHRH decline: GH secretion drops roughly 14% per decade after age 30, a process called somatopause. This drives interest in GHRH analogs and growth hormone secretagogues like ipamorelin.
  • MOTS-c decreases: As noted, circulating levels drop approximately 21% between young adulthood and the eighth decade.
  • Oxytocin may decline: Some data suggest reduced oxytocin receptor expression with aging, though circulating levels are less consistently reduced.
  • Antimicrobial peptide production shifts: LL-37 expression in skin declines with age, potentially contributing to increased infection susceptibility in elderly individuals.
  • Beta-endorphin production decreases: This may partly explain the increased pain sensitivity reported by some older adults.
  • GLP-1 response blunts: The incretin effect weakens with age, contributing to the age-related rise in type 2 diabetes risk.

These changes are not irreversible fates. Exercise, for example, acutely raises endorphin, MOTS-c, and GLP-1 levels regardless of age. Vitamin D supplementation can restore LL-37 expression in deficient individuals.

Therapeutic Mimicry: Drugs Based on Your Own Peptides

Many successful drugs are synthetic versions of — or are inspired by — endogenous peptides. This strategy works because the body already has the receptors and signaling pathways in place. The drug simply mimics or blocks what a natural peptide does.

Endogenous PeptideDrug AnalogIndication
GLP-1Semaglutide (Ozempic, Wegovy)Type 2 diabetes, obesity
GLP-1 + GIPTirzepatide (Mounjaro, Zepbound)Type 2 diabetes, obesity
VasopressinDesmopressinDiabetes insipidus, bedwetting
SomatostatinOctreotideAcromegaly, carcinoid tumors
AmylinPramlintide (Symlin)Type 1 and 2 diabetes
OxytocinPitocinLabor induction
GHRHCJC-1295Research (GH secretion)
GnRHLeuprolide (Lupron)Prostate cancer, endometriosis
CGRPErenumab (blocks CGRP receptor)Migraine prevention
InsulinInsulin glargine, lispro, aspartDiabetes

The peptide therapeutics market was projected to reach $49.68 billion by 2026, driven largely by GLP-1 receptor agonists. Understanding endogenous peptides is the foundation for understanding these drugs.

FAQ

How many endogenous peptides does the human body produce? No one has an exact count. The human genome encodes roughly 90 neuropeptide precursor genes, dozens of peptide hormone genes, multiple antimicrobial peptide genes, and at least 8 mitochondrial-derived peptides. When you include all the proteolytic fragments that have documented biological activity, the total likely exceeds several hundred distinct bioactive peptides.

Are endogenous peptides the same as hormones? Not all endogenous peptides are hormones. Hormones are defined by their mode of action — they are secreted into the bloodstream and act on distant target tissues. Neuropeptides act locally in the nervous system. Antimicrobial peptides act at sites of infection. Mitochondrial-derived peptides can act within the cell that produces them. "Endogenous peptide" is a broader term that encompasses all of these.

Can you boost your body's natural peptide production? In some cases, yes. Exercise reliably increases beta-endorphin, MOTS-c, and GLP-1 levels. Adequate vitamin D supports LL-37 production. Protein-rich meals stimulate CCK, PYY, and GLP-1 release. Sleep and stress management support healthy cortisol and oxytocin rhythms. However, there is no general "peptide booster" — each peptide system has its own specific regulators.

What happens when endogenous peptide levels are too low or too high? Imbalances in endogenous peptide levels underlie many diseases. Insulin deficiency causes type 1 diabetes. Excess cortisol (driven by excess CRH and ACTH) causes Cushing's syndrome. Deficient GnRH causes hypogonadism. Overactive substance P signaling contributes to chronic pain syndromes. Most endocrine disorders can be understood as disruptions in peptide signaling.

Are all body peptides encoded in nuclear DNA? No. Mitochondrial-derived peptides (humanin, MOTS-c, SHLPs) are encoded in mitochondrial DNA. Since mitochondria are inherited maternally, these peptides represent a maternal genetic contribution to metabolic regulation that is separate from the nuclear genome.

The Bottom Line

Your body is a peptide factory. From the beta-endorphins that dull pain after a hard workout to the GLP-1 that tells your pancreas to release insulin after a meal, from the LL-37 that kills bacteria on your skin to the MOTS-c that your mitochondria release during exercise — endogenous peptides are everywhere, doing everything.

They are organized into functional families: hormones that signal through the bloodstream, neuropeptides that wire the brain, antimicrobial peptides that defend against infection, and mitochondrial-derived peptides that bridge organelle-to-nucleus communication. Most begin as larger precursor proteins and are carved into their active forms by tissue-specific enzymes.

Understanding this endogenous peptide inventory is the starting point for understanding peptide therapeutics, peptide supplements, and your own physiology. The drugs that are reshaping medicine — semaglutide, tirzepatide, CGRP antibodies — all work by mimicking, modifying, or blocking the peptides your body already makes.

For a broader introduction to peptide science, see our complete beginner's guide to peptides.

References

  1. Fricker LD. Neuropeptide-processing enzymes: applications for drug discovery. AAPS J. 2005. https://pmc.ncbi.nlm.nih.gov/articles/PMC3418817/
  2. The neuropeptides. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK28247/
  3. Neuropeptide. Wikipedia. https://en.wikipedia.org/wiki/Neuropeptide
  4. Foster SR et al. Discovery of human signaling systems: pairing peptides to G protein-coupled receptors. Cell. 2019;179(4):895-908. https://www.sciencedirect.com/science/article/pii/S0092867419311262
  5. Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-454. https://www.sciencedirect.com/science/article/pii/S1550413115000613
  6. Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470. https://www.nature.com/articles/s41467-020-20790-0
  7. Cathelicidin LL-37: an antimicrobial peptide with a role in inflammatory skin disease. Ann Dermatol. 2012. https://pmc.ncbi.nlm.nih.gov/articles/PMC3346901/
  8. Immunomodulatory properties of defensins and cathelicidins. Molecules. 2020. https://pmc.ncbi.nlm.nih.gov/articles/PMC7121507/
  9. Physiology, hypothalamus. StatPearls. NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK535380/
  10. Identifying and measuring endogenous peptides through peptidomics. Anal Bioanal Chem. 2023. https://pmc.ncbi.nlm.nih.gov/articles/PMC10614431/
  11. Physiology, adrenocorticotropic hormone (ACTH). StatPearls. NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK500031/