Neuropeptide Y
Neuropeptide Y (NPY)
Written by Aaron CuhaReviewed Sep 2026
Also known as: NPY, Neuropeptide tyrosine
The most potent appetite-driving peptide known when injected into a rodent brain. The one large human test of the idea, a 52 week trial of a Y5 receptor blocker in 1,661 overweight and obese adults, produced weight loss its own authors called not clinically meaningful. The only trial of NPY itself in people gave it intranasally to 26 patients with PTSD.
Overview
Neuropeptide Y is one of the most abundant neuropeptides in the mammalian brain and a co-transmitter released alongside noradrenaline from sympathetic nerves. It is a 36 amino acid peptide and it belongs to one structural family with peptide YY and pancreatic polypeptide, which is why the three are almost always discussed together.
What it does in a rodent is not subtle. Injected into the hypothalamus it is the strongest orexigenic signal anyone has identified, and it rises with fasting and falls with feeding. That result is thirty years old, it replicates, and it is the reason the pharmaceutical industry spent a long time trying to block it.
That attempt has an answer, and it is the most useful thing on this page. Merck took a selective Y5 receptor antagonist, MK-0557, through positron emission tomography dosing work and a 12 week dose-ranging study, then ran a 52 week randomised, double-blind, placebo-controlled trial in 1,661 overweight and obese patients. The weight loss was statistically significant and, in the authors' own words in the title of the paper, not clinically meaningful. Companion trials found it added nothing to orlistat or sibutramine and did not prevent regain after a very low calorie diet.
NPY itself has been given to people only in small studies. Twenty six patients with post-traumatic stress disorder received intranasal NPY or placebo in a single ascending dose crossover trial; it was tolerated up to the top dose and higher doses favoured NPY on one anxiety scale and not on the other. Separately, NPY infused into the forearm artery of eighteen volunteers constricted blood vessels dose-dependently, and a DPP-4 inhibitor made that constriction stronger, which is a safety observation about diabetes drugs rather than a therapy.
The longevity claim attached to NPY in supplement writing traces to rodent hypothalamic autophagy work whose own authors ended their title with a question mark.
Mechanism of action
NPY signals through a family of class A G protein-coupled receptors. In humans, Y1, Y2, Y4 and Y5 are functional. Y1 and Y5 drive feeding; Y2 sits presynaptically on arcuate NPY neurons and is inhibitory, which is the receptor peptide YY 3-36 prefers and the reason those two peptides of the same family push appetite in opposite directions. Y1 also mediates vasoconstriction in the periphery, where NPY is released with noradrenaline from sympathetic terminals. Dipeptidyl peptidase-4 cleaves NPY to NPY 3-36, converting a Y1-active vasoconstrictor into a Y2-preferring peptide that reduces noradrenaline release, so inhibiting DPP-4 shifts the balance back toward vasoconstriction. Central injection in rodents also stimulates hypothalamic autophagy through Y1 and Y5, which is the mechanistic basis of the ageing claim and is a rodent finding.
Human evidence
One small phase 1 crossover trial of NPY itself in PTSD, forearm infusion physiology in eighteen volunteers, and one large 52 week randomised trial of a drug that blocks an NPY receptor, which failed.
- MK-0557, a selective Y5 antagonist: 52 weeks, 1,661 overweight and obese patients, randomised, double-blind, placebo-controlled. Weight loss statistically significant and, per the authors, not clinically meaningful.
- Companion randomised trials of the same compound found it did not augment the weight loss achieved with orlistat or sibutramine, and did not prevent weight regain after very low calorie diet induced loss.
- Intranasal NPY in PTSD: 26 randomised, 24 completed, single ascending doses to 9.6 mg, tolerated, with a significant dose by treatment interaction on the Beck Anxiety Inventory and none on the State-Trait Anxiety Inventory.
- Intra-arterial NPY in 18 volunteers produced dose-dependent forearm vasoconstriction, potentiated by the DPP-4 inhibitor sitagliptin.
- No human study has administered NPY for appetite, body weight, metabolic health or ageing.
What this does not tell you: The PTSD trial was a single dose tolerability and signal-detection study in 26 people, with a positive result on one anxiety instrument and a null on the other, and no follow-up trial resolved here. Nothing establishes that NPY administration changes any clinical outcome in any condition. The obesity literature tests receptor blockade rather than the peptide, and its answer was negative. The vasoconstriction data are a reason for caution about peripheral NPY exposure, not an indication.
Reading the research record
NPY is the clearest case on this site of a molecule whose physiology is beyond dispute and whose therapeutic record is close to empty, and the gap is worth understanding because it recurs.
The rodent evidence is genuinely strong. Central NPY injection produces the largest feeding response of any known peptide. Any reasonable person reading that literature in the 1990s would have concluded that blocking NPY was a serious obesity strategy, and the industry agreed.
Then it was tested. The Y5 programme ran the full sequence, receptor occupancy imaging, dose finding, a year-long randomised trial in over sixteen hundred patients, and add-on trials against two existing weight loss drugs. The result was a small, statistically detectable, clinically irrelevant effect, and the authors said so in the title. Redundancy is the usual explanation: appetite is defended by many overlapping signals, so removing one changes little.
The consequence for a reader is specific. When you see NPY described as the body's most powerful appetite hormone, that is true and it is also the reason a drug aimed at it failed. Potency in a rodent brain injection does not predict tractability in a person.
The ageing claim deserves the same treatment. It rests on hypothalamic autophagy in rodents, proposed by its authors as a hypothesis with a question mark. No lifespan study and no human study supports it.
The evidence, charted
Fig. 1 · evidence composition
3of 5 citations (60%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 4 distinct years, 2006 to 2018, counted from the citation list on this page. The newest citation on file is from 2018, more than five years ago; the published record may have gone quiet.
Fig. 3 · legal status at a glance
US
Not approved
UK
Not approved
AU
Not approved
CA
Not approved
Not approved in any of the four jurisdictions shown. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Human2006
Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults
The definitive human test of the NPY appetite hypothesis, and a negative one. After a positron emission tomography dosing study and a 12 week dose-ranging study identified 1 mg per day as the optimal dose, MK-0557 was taken into a 52 week, multicentre, randomised, double-blind, placebo-controlled trial in 1,661 overweight and obese patients. The weight loss was statistically significant at 52 weeks but the authors state plainly that its magnitude was not clinically meaningful, and conclude that targeting the Y5 receptor alone is unlikely to produce therapeutic efficacy. The trial was run by Merck, whose employees are among the authors.
Cell Metabolism - Human2018
A Randomized Dose-Ranging Study of Neuropeptide Y in Patients with Posttraumatic Stress Disorder
The only trial of NPY itself in people resolved here. Twenty six individuals with PTSD were randomised into one of five single ascending dose cohorts of intranasal NPY, from 1.4 mg to 9.6 mg, each dosed with NPY and with placebo a week apart under double-blind crossover conditions, with assessment after a trauma script provocation. Twenty four completed both days. NPY was tolerated to the highest dose. There was a significant treatment by dose interaction favouring NPY on the Beck Anxiety Inventory (F1,20 = 4.95, P = .038) and no significant interaction on the State-Trait Anxiety Inventory. The authors describe this as suggesting NPY may be associated with anxiolytic effects and call for future studies. Registered as NCT01533519, a phase 1 study, completed.
International Journal of Neuropsychopharmacology - Human2018
DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition
Eighteen non-smokers, twelve healthy controls and six with type 2 diabetes, in randomised double-blind placebo-controlled crossover studies of sitagliptin against placebo, with NPY infused into the brachial artery and forearm blood flow measured by plethysmography. NPY caused dose-dependent vasoconstriction, and sitagliptin significantly potentiated it during enalaprilat and during valsartan. The authors suggest this could contribute to the cardiovascular effects of DPP-4 inhibitors in patients taking an ACE inhibitor or an angiotensin receptor blocker. This is a mechanistic safety finding about diabetes drugs, not a therapeutic result for NPY.
Hypertension - Animal2015
NPY/neuropeptide Y enhances autophagy in the hypothalamus: a mechanism to delay aging?
The source of the NPY longevity claim, and the authors put the question mark in their own title. They report that NPY stimulates autophagy in rodent hypothalamus, mediates caloric restriction induced autophagy in hypothalamic neurons, and acts through Y1 or Y5 receptors. Their proposal that modulating NPY could extend longevity is stated as a hypothesis. There is no lifespan experiment here and no human work.
Autophagy - Review2012
Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis
The standard review placing NPY in its family with peptide YY and pancreatic polypeptide, and the reason this page cannot be read in isolation from the PYY page. The same receptor family carries opposite appetite signals depending on which member binds which receptor.
Neuropeptides
Frequently asked questions
Can you take neuropeptide Y for appetite or weight?
No, and the direction implied is backwards. NPY increases appetite. The therapeutic idea was to block it, and that was tested: a Y5 receptor antagonist in 1,661 patients over 52 weeks produced weight loss the investigators themselves described as not clinically meaningful. There is no approved drug at any NPY receptor.
Does NPY slow ageing?
There is no evidence that it does in any species. The claim comes from work showing NPY stimulates autophagy in the rodent hypothalamus, published under a title that ends in a question mark, with the longevity link stated by the authors as a hypothesis. No lifespan experiment and no human study supports it.
Has NPY been given to humans at all?
Yes, twice in the work resolved here. Intranasal NPY in 26 patients with PTSD, a phase 1 single ascending dose crossover study, where it was tolerated to 9.6 mg and higher doses favoured NPY on one anxiety scale but not the other. And intra-arterial infusion in 18 volunteers, where it constricted forearm blood vessels, which was a physiology experiment rather than a treatment.
How is NPY different from PYY?
They are structural relatives in the same family and they point in opposite directions. NPY acts at Y1 and Y5 to drive feeding. PYY is cleaved by DPP-4 to PYY 3-36, which prefers the inhibitory Y2 receptor on NPY neurons and reduces food intake. Same receptor family, opposite effect, which is why the two pages belong next to each other.
Is it legal to buy?
NPY is an endogenous neuropeptide rather than an approved product anywhere, and unlike most hormones in this class there is no approved medicine acting at its receptors to point to. Anything sold as NPY is unapproved material of unverified identity, and the only human dosing experience is a single phase 1 trial.