Neuropeptide Y_Dosage, benefits & legal status

The useful thing about neuropeptide Y is the gap between how powerful it looks in animals and how little came of it in people. Understanding why the gap exists is worth more than any dose.

1. 01
   A family of three, all built the same way

   Neuropeptide Y, peptide YY and pancreatic polypeptide are all 36 amino acids long and all end in an amidated tyrosine. Neuropeptide Y is cut from a 97 amino acid precursor at residues 29 to 64. The shared architecture is why they cross-react at each other's receptors, and why a claim about one of them frequently gets attached to another. The family members overlap in sequence by roughly 60 to 70 percent depending on which pair and which species are compared.
2. 02
   Four receptors, and a fifth that does not exist

   Humans have four functional receptors in this family: Y1, Y2, Y4 and Y5. Feeding behavior is attributed mainly to Y5 and Y1, and blood vessel constriction to Y1. A Y3 receptor appears in older literature and was never cloned; there is no human gene for it. What is called Y6 is a pseudogene in humans, though it is functional in mice and rabbits. A page or product claiming an action at Y3 is describing something that was not found to exist.
3. 03
   The rodent result, and the detail that undermines it

   Injected into the paraventricular hypothalamus of a rat, neuropeptide Y produces the most powerful stimulation of feeding described for any peptide. That is a real and reproducible finding from 1985. The qualifier is the route. The peptide was delivered directly into the brain, past the barrier that would normally keep it out. Nothing about that result says what happens when the peptide is in the bloodstream, and no human study of neuropeptide Y and appetite exists.
4. 04
   What happened when companies blocked it

   If this peptide drives eating, an antagonist should reduce it. Merck tested MK-0557 in overweight and obese adults and published in Cell Metabolism in 2006; the title is Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults. Shionogi tested velneperit against orlistat in 486 people in a phase 2 trial that completed in February 2011 and posted no results. Two serious attempts, no drug.
5. 05
   The family tension nobody resolves cleanly

   Here is the part worth sitting with. Neuropeptide Y stimulates appetite through Y5 and Y1 when placed in the brain. Its close relative peptide YY, in the fragment form PYY(3-36), suppresses appetite from the bloodstream through Y2. Same family, same receptor system, opposite effects on eating depending on the peptide, the receptor and the side of the blood-brain barrier involved. The 2002 result for PYY(3-36) was itself publicly disputed in 2004 and defended, so even that half is less settled than it is usually presented.
6. 06
   The one human trial of the peptide itself

   A phase 1 study at Mount Sinai gave intranasal neuropeptide Y to 26 people with post-traumatic stress disorder in a randomized, double-blind, placebo-controlled crossover design, with tolerability and side effects as the primary outcome. It completed in January 2016. No results were posted to the registry, and the investigators published separately. A 26-person phase 1 safety study is where this peptide's human evidence begins and ends.