Enterostatin
The fat-digestion by-product that made rats eat less fat, and did nothing measurable when people took it
Enterostatin is a five-amino-acid peptide snipped off procolipase, the helper protein that pancreatic lipase needs to digest fat. In the early 1990s rats given enterostatin ate less fat but not less carbohydrate or protein, which made it a candidate fat-specific appetite signal. Two small human trials, one intravenous and one by mouth, found no effect on how much people ate or burned. Studies that measured it in human blood and spinal fluid gave inconsistent numbers, and mice that cannot make it eat normally. It has no approval anywhere.
Used in human trials: 15 mg, Three times a day, Oral (Study: oral enterostatin in adults who prefer fatty food) Details ↓
Recommended Dosing
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
Fat digestion depends on pancreatic lipase, and lipase works on fat droplets only with a partner protein, colipase. The pancreas secretes colipase in an inactive form, procolipase. In the gut, trypsin trims five amino acids off its front end to switch it on, and that leftover pentapeptide is enterostatin. Because a fatty diet increases procolipase production, its by-product looked like a natural signal of how much fat had been eaten, and a 1997 review traced it into the lymph and blood after meals.
The animal results that made enterostatin interesting arrived in 1991. Injected into the abdomen of rats eating a high-fat diet, it reduced food intake in proportion to the dose; with a choice of foods, the rats cut their fat intake and left carbohydrate and protein alone. Injected into the brain ventricles, it reduced high-fat but not low-fat eating, and nine days of brain infusion lowered fat intake, body weight and fat pads. Sheep ate less after brain injection too. Later work tied the effect to the melanocortin system in the brain, to cholecystokinin receptors and to the vagus nerve, and proposed the beta subunit of F1-ATPase, part of the mitochondrial energy-producing enzyme, as a binding protein.
The effect was never simple. Rats responded only if they had been eating fat for some time; brain injection in rats that had not been fasted increased snacking rather than suppressing it; and the dose-response in sheep and rats was U-shaped, with high doses doing nothing. Mice engineered to lack enterostatin, while keeping colipase, grew normally, ate normally on high- and low-fat diets and became obese on a fatty diet just as normal mice did. Their main difference was higher blood cholesterol, and enterostatin given by mouth lowered cholesterol in mice fed a cholesterol-rich diet.
In people, the evidence is short. A 1995 Swedish trial gave 18 obese men intravenous enterostatin or placebo just before a test meal and found no change in how much they ate or how full they felt. A 2003 Dutch trial gave 12 healthy adults who liked fatty food enterostatin by mouth three times a day for four days on an unrestricted high-fat diet; energy intake, fat intake, hunger, energy expenditure and fat burning were all the same as on placebo. Measurement studies disagree on basic numbers: one found enterostatin-like material in human spinal fluid that was not any known enterostatin, another reported micromolar levels of the rat form, and blood levels in two obesity studies differed by more than tenfold.
Enterostatin therefore remains a well-studied rodent signal with no demonstrated effect in humans. It is not approved anywhere, and the doses below are the two amounts that human trials gave, both without benefit. They describe the research, not a treatment.
Mechanism of Action
Enterostatin is released in the gut when procolipase is activated during fat digestion; in rodents it acts on the vagus nerve and the brain to reduce fat intake.
Formed during fat digestion
Trypsin cuts procolipase into colipase, the cofactor pancreatic lipase needs, and the enterostatin pentapeptide; fatty diets raise procolipase output (PMID 9285845).
Brain fat-intake circuits
In rodents it reduced fat intake through melanocortin signalling, cutting AgRP and activating alpha-MSH neurons (PMID 17113194).
Binding partner
Binds the beta subunit of the F1-ATPase found on cell membranes, proposed as its receptor (PMID 15572201).
Insulin and cholesterol
Reduced insulin release from rat islets and lowered serum cholesterol in mice through a cholecystokinin-1-receptor-dependent route (PMIDs 9725641, 18824202).
Published Research
Studies of enterostatin read from their PubMed abstracts: the two human trials, human measurement studies in blood and spinal fluid, the rat, mouse and sheep feeding work, mechanism and binding studies, and three reviews. Many animal studies used the rat sequence VPDPR rather than the human APGPR; each card says what was tested where the abstract does.
Oral enterostatin for four days
In a double-blind placebo-controlled crossover, 12 healthy adults who preferred fatty food took enterostatin by mouth three times a day for four days while eating a high-fat diet freely. Energy intake, macronutrient mix, hunger, satiety, 24-hour energy expenditure and respiratory quotient were the same on enterostatin and placebo, and weight loss did not differ.
Intravenous enterostatin before a meal
Eighteen obese but otherwise healthy men received intravenous enterostatin at two doses or placebo, in random order, just before a test meal on an eating monitor. No measure of intake or appetite rating changed. The authors list possible reasons: the peptide may not reach its site of action, timing, or only people with particular fat preferences might respond.
Higher in obese women
In 38 women spanning lean to severely obese, fasting serum VPDPR-like enterostatin was higher in obese than lean women (about 1,516 against 603 nmol/L). The rise in APGPR after a meal was larger in lean women, which the authors read as reduced release with eating in obesity.
Unchanged by weight loss
In 31 overweight adults on a 23-week energy-restricted diet built around an oat-based soup, weight, glucose, insulin and LDL cholesterol fell, but plasma enterostatin stayed between about 25 and 30 nmol/L at all five sampling times.
In spinal fluid, but not the known forms
Using antibodies against the VPDPR and APGPR forms and chromatography, the authors detected enterostatin-like immunoreactivity in human cerebrospinal fluid for the first time. On further analysis it was not APGPR, VPGPR or VPDPR but another peptide resembling VPDPR.
A capillary electrophoresis assay
A fluorescence-based capillary electrophoresis method separated the three enterostatin pentapeptides. Applied to 23 human cerebrospinal fluid samples, it reported VPDPR at 24 to 51 micromolar, mean about 42.
Rats eat less fat
Injected into the abdomen of fasted rats, VPDPR reduced intake of a high-fat diet in a dose-dependent way, lasting over six hours at higher doses, but did not affect a high-carbohydrate low-fat diet. Rats choosing among three macronutrient diets cut fat only, and the free amino acids had no effect.
Brain injection and diet choice
Given into the brain ventricles of fasted rats with a free choice of diets, VPDPR cut intake of the high-fat diet by 45% and left the low-fat diet untouched. A four-residue version lacking the final arginine lost the effect.
Nine days of brain infusion
Continuous infusion into the brain ventricles of rats choosing between high- and low-fat diets reduced high-fat intake, most on day four, with no compensating rise in low-fat intake. Body weight, fat pads, liver weight, triglycerides and insulin fell, and corticosterone rose.
Works only after fat adaptation
Rats responded to brain enterostatin only if they had been adapted to a high-fat diet. Rats adapted to a high-carbohydrate diet did not respond even after three weeks on fat, and fat-adapted rats lost the response once switched to carbohydrate, suggesting a fat-driven change is needed first.
The opposite result in fed rats
In rats that had not been food-deprived, brain doses up to 32 micrograms did not reduce intake of a high-fat cookie at any dose, and the top dose increased it at 30 minutes. The authors note this conflicts with earlier reports.
Sheep eat less
In sheep, a 2-microgram injection into the brain ventricles cut feed intake by a third to two-thirds in the following hour, while lower and higher doses had no significant effect, a narrow window similar to that seen in rats.
Acts through melanocortin signalling
Enterostatin did not reduce intake in mice lacking the melanocortin-4 receptor, and a melanocortin receptor blocker stopped its effect in rats. It activated alpha-MSH neurons and lowered AgRP expression in the hypothalamus, the amygdala and a neuronal cell line.
Released into rat blood after meals
Plasma enterostatin rose in fasted rats after any meal, more and for longer after high-fat meals, and tracked fat intake. Chromatography showed it matched the synthetic peptide, and a single protein of about 66 kDa in plasma bound it.
Reaches the brain in small amounts
After intravenous injection of radiolabelled VPDPR in rats, low levels of radioactivity reached many brain areas, highest in the frontal cortex, hippocampus and cerebellum; radioactivity was found in all tissues and was highest in the pancreas.
Mice that cannot make it
Mice lacking enterostatin but keeping colipase were healthy and fertile, grew normally, chose diets normally and became obese on a high-fat diet like normal mice. They had higher total and non-HDL cholesterol and lower HDL, and giving enterostatin improved the survival of pups lacking procolipase.
Lowers cholesterol in mice
Given by mouth to mice on a high-cholesterol diet for three days, the human form APGPR lowered serum cholesterol. A cholecystokinin-1 receptor blocker prevented the effect although APGPR itself does not bind that receptor, and the rat form VPDPR behaved the same way.
A candidate receptor
Enterostatin bound the isolated beta subunit of F1-ATPase with a dissociation constant of 150 nM but not the assembled enzyme. Analogues that suppressed feeding promoted binding of beta-casomorphin to the subunit, while those that did not displaced it, and the subunit was found on cell-surface membranes in rat liver and amygdala.
Damps insulin release from islets
In isolated rat islets, enterostatin from 10^-9 to 10^-5 M reduced glucose-stimulated insulin release in a dose-dependent way and also blunted release driven by glibenclamide and other stimulants. It lowered islet cyclic AMP, and adding a cyclic AMP analogue blocked the effect.
A peptide regulating fat intake
This review describes enterostatin's formation from procolipase, its release with fatty diets, its fat-selective effect across species through vagal and brain pathways, and chronic reductions in fat intake, weight and body fat, and notes that obese people secrete less procolipase after a test meal.
Target mechanisms
The authors argue that fat digestion itself limits fat intake and that enterostatin prevents overconsumption of fat, proposing two targets: an opioid pathway and the beta subunit of the F1F0-ATP synthase, at which beta-casomorphin competes with it.
Enterostatin and apolipoprotein AIV
This review summarises a decade of evidence that enterostatin, formed when trypsin cleaves procolipase, inhibits food and especially fat intake, and sets it beside apolipoprotein AIV, another gut protein released during fat absorption that acts as a satiety signal.
Dosing Data
These are the only amounts given to people in published trials. Neither changed food intake, appetite or energy expenditure, so they are not effective doses; they show what was tested.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Enterostatin is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
No worked example: none of the doses on this page is a fixed amount in mg or mcg injected under the skin or into a muscle (the routes given are: intravenous, oral). There is no home-mixing step to show. The reconstitution calculator does the arithmetic for any vial.
Source: the route and amount of each dose row in Dosing Data below.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Enterostatin, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Enterostatin stays intact once mixed.
How it is taken
As it was given in human studies: Oral (Three times a day; Study: oral enterostatin in adults who prefer fatty food); Intravenous (Once, just before a test meal; Study: intravenous enterostatin in obese men).
For injection technique, sites and needle disposal, see the mixing guide.
Source: Used in human trials: the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: not established by a measurement cited on this entry.
How long the doses were given: Study: oral enterostatin in adults who prefer fatty food: 4 days, on a high-fat diet; no effect on intake or energy expenditure; Study: intravenous enterostatin in obese men: Single sessions in a crossover; no effect on intake.
When effects appear: unknown; no source on this page gives a time to effect for Enterostatin. Results reported in the studies are under Published Research.
Source: Used in human trials, the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: No change in food intake, appetite, energy expenditure or weight compared with placebo in either human trial (PMIDs 12844393, 7741534); In rats, brain doses outside a narrow range did nothing, and in fed rats a high dose increased high-fat snacking (PMIDs 8844782, 8071183); In rat islets it reduced insulin release, an effect not studied in people (PMID 9725641). Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Enterostatin. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“The two human trials reported no effect on intake or energy use; their abstracts do not report adverse events”).
Interactions
Unknown: a PubMed search for human interaction studies of Enterostatin (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Enterostatin products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Enterostatin's expected mass, 496.6 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not a medicine anywhere: no approval in the sources read). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
The two human trials reported no effect on intake or energy use; their abstracts do not report adverse events.
Contraindications & Cautions
Enterostatin is not an approved medicine anywhere.
Legal Status
Enterostatin is a research peptide that never reached approval.
Frequently Asked Questions
?What is enterostatin?
A five-amino-acid peptide released when procolipase, the partner protein of pancreatic lipase, is switched on in the gut during fat digestion. In humans its sequence is APGPR.
?Does it reduce fat cravings?
In rats it selectively reduced fat intake. In the two human trials, one by vein and one by mouth for four days, it changed nothing: people ate the same amount and the same mix of foods as on placebo.
?Why did it work in rats and not people?
The authors of the human trials suggest it may not reach its site of action, the timing may matter, or only some people respond. Rat responses were themselves fragile, appearing only after fat adaptation and within a narrow dose window.
?Does the body need enterostatin?
Mice unable to make it grew, ate and gained weight normally, though their cholesterol was higher. So it does not appear essential for appetite control, at least in mice.
?Is it the same as colipase?
No. Colipase is the larger protein left after enterostatin is cut away; colipase helps lipase digest fat, and enterostatin is the small by-product.
?Can it be bought?
It is not an approved medicine anywhere. Anything sold under the name is a research chemical with no proven effect in people.
References
- [clinical-trial] Kovacs EM, et al. "The effects of enterostatin intake on food intake and energy expenditure." Br J Nutr, 2003;90(1):207-14. PMID: 12844393.
- [clinical-trial] Rössner S, et al. "Intravenous enterostatin does not affect single meal food intake in man." Appetite, 1995;24(1):37-42. PMID: 7741534.
- [pubmed] Prasad C, et al. "Hyperenterostatinemia in premenopausal obese women." J Clin Endocrinol Metab, 1999;84(3):937-41. PMID: 10084574.
- [pubmed] Rytter E, et al. "Changes in plasma insulin, enterostatin, and lipoprotein levels during an energy-restricted dietary regimen including a new oat-based liquid food." Ann Nutr Metab, 1996;40(4):212-20. PMID: 8886249.
- [pubmed] Imamura M, et al. "Distribution and characterization of enterostatin-like immunoreactivity in human cerebrospinal fluid." Peptides, 1998;19(8):1385-91. PMID: 9809653.
- [pubmed] Zhao S, et al. "Determination of enterostatin in human cerebrospinal fluid by capillary electrophoresis with laser induced fluorescence detection." Fresenius J Anal Chem, 2001;369(3-4):220-4. PMID: 11293697.
- [pubmed] Okada S, et al. "Enterostatin (Val-Pro-Asp-Pro-Arg), the activation peptide of procolipase, selectively reduces fat intake." Physiol Behav, 1991;49(6):1185-9. PMID: 1896500.
- [pubmed] Erlanson-Albertsson C, et al. "Pancreatic procolipase propeptide, enterostatin, specifically inhibits fat intake." Physiol Behav, 1991;49(6):1191-4. PMID: 1896501.
- [pubmed] Lin L, et al. "Chronic ICV enterostatin preferentially reduced fat intake and lowered body weight." Peptides, 1997;18(5):657-61. PMID: 9213358.
- [pubmed] Lin L, et al. "Chronic ingestion of dietary fat is a prerequisite for inhibition of feeding by enterostatin." Am J Physiol, 1998;275(2):R619-23. PMID: 9688701.
- [pubmed] Rice HB, et al. "Intracerebroventricular enterostatin stimulates food intake in non-food-deprived rats." Peptides, 1996;17(5):885-8. PMID: 8844782.
- [pubmed] Miner JL, et al. "Reduction of feed intake in sheep by enterostatin, the procolipase activation peptide." J Anim Sci, 1994;72(6):1578-82. PMID: 8071183.
- [pubmed] Lin L, et al. "Enterostatin inhibition of dietary fat intake is modulated through the melanocortin system." Peptides, 2007;28(3):643-9. PMID: 17113194.
- [pubmed] Mei J, et al. "Plasma enterostatin: identification and release in rats in response to a meal." Obes Res, 2002;10(7):688-94. PMID: 12105292.
- [pubmed] Koizumi M, et al. "Uptake across the blood-brain barrier and tissue distribution of enterostatin after peripheral administration in rats." Physiol Behav, 2002;77(1):5-10. PMID: 12213496.
- [pubmed] Miller R, et al. "Enterostatin deficiency increases serum cholesterol but does not influence growth and food intake in mice." Am J Physiol Endocrinol Metab, 2009;297(4):E856-65. PMID: 19622781.
- [pubmed] Takenaka Y, et al. "Enterostatin reduces serum cholesterol levels by way of a CCK(1) receptor-dependent mechanism." Peptides, 2008;29(12):2175-8. PMID: 18824202.
- [pubmed] Park M, et al. "The F1-ATPase beta-subunit is the putative enterostatin receptor." Peptides, 2004;25(12):2127-33. PMID: 15572201.
- [pubmed] Ookuma M, et al. "Inhibition of insulin release by enterostatin." Int J Obes Relat Metab Disord, 1998;22(8):800-5. PMID: 9725641.
- [review] Erlanson-Albertsson C, et al. "Enterostatin--a peptide regulating fat intake." Obes Res, 1997;5(4):360-72. PMID: 9285845.
- [review] Berger K, et al. "Enterostatin and its target mechanisms during regulation of fat intake." Physiol Behav, 2004;83(4):623-30. PMID: 15621068.
- [review] Liu M, et al. "The role of enterostatin and apolipoprotein AIV on the control of food intake." Neuropeptides, 1999;33(5):425-33. PMID: 10657520.
- [other] UniProt P04118 (COL_HUMAN), propeptide residues 18-22, enterostatin, activation peptide; read October 28, 2026. https://www.uniprot.org/uniprotkb/P04118/entry
- [other] PubChem CID 3082883, Enterostatin: formula C21H36N8O6, molecular weight 496.6. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/3082883
Sources & Citations
Every study on this page was read from its PubMed record on October 29, 2026. Sequence from UniProt, formula and weight from PubChem; status from Drugs@FDA (openFDA) and the EMA medicines list. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.