Asking directly, because I could not find a straight answer: Why appetite effects are mostly central
A follow-up question about appetite effects that I did not know to ask the first time.
The earlier thread answered what I asked. What I should have asked is below, and I think it is the one that matters.
The arithmetic in post #2 is right; the assumption feeding it is the part to check.
Endogenous versus pharmacological receptor engagement differ in magnitude and in duration by orders of magnitude. Arguments from "it is a natural hormone" do not survive that.
Caveat: everything above assumes the paperwork is what it says it is.
Trying to state the appetite effects position in a way that someone who disagrees would recognise as fair, because I do not think the version in this thread passes that test.
Fine by me. I had wanted a stronger conclusion and there is not one available.
Appetite effects looks different depending on whether you are reading the primary literature or the summaries of it, and the difference is not in our favour.
Narrowing post #6, because the general version has more than one answer.
Half-life extension by albumin binding through a fatty acid chain trades free fraction for duration. It is an engineering solution with a cost, and the cost is that the bound fraction is not active.
That is all I can say without guessing.
Everything in post #4 holds. The case it does not cover is the one I have.
Where a mechanism is proposed to explain an effect, the useful follow-up is what observation would distinguish it from the alternative. Most mechanistic threads here never get asked that.
Nothing above should be read as advice about what anyone else should do.
Confirming post #6 from a second method, which matters more than confirming it from a second person.
Nothing in receptor biology tells you what is in the vial, which is worth remembering when a mechanistic thread starts being used to justify a sourcing decision.
Genuinely open to being wrong about this one.
I had written a reply contradicting post #8 and deleted it. Here is what survived.
Long-term receptor changes: very little is known about what happens to receptor expression, signalling, and downstream effects over years of exposure to these compounds. That is exactly the knowledge gap phase 3 trials exist to fill.
The part I am sure of is shorter than the part I have written.
Post #7 and I disagree about the size of the effect, not about the direction.
The documentation on appetite effects is better than this thread and I say that as someone who has posted in the thread.
Taking post #11 at face value and following it one step further.
The area postrema sits outside the blood-brain barrier and is where a great deal of the nausea signalling in this class originates. That is why the effect is central and not gastric irritation.
It is one reading of the data and not the only reasonable one.
Something worth flagging about appetite effects: the strongest-sounding claims in this thread are the ones with no source attached, which is the usual pattern and not a coincidence.
I have three months of notes on appetite effects and the honest summary is that the trend is real and the week-to-week numbers are noise. I nearly drew the opposite conclusion from the first fortnight.
Worth separating two things that post #11 runs together.
Central versus peripheral action: GLP-1 agonism works through both central nervous system effects (appetite) and peripheral effects (gastric motility, insulin). The balance is not fully characterised.
A modest claim, modestly supported.
Mechanistic plausibility has a poor record of predicting clinical outcomes across this whole field. It is a good reason to run the trial and a bad reason to skip it.
I came in to disagree and I am leaving without a disagreement.
Where the appetite effects discussion usually stalls is that nobody wants to say "I do not know" and everyone is willing to say "it varies". Those are the same sentence with different clothes on.
Glucose dependence is the property that distinguishes incretin-mediated insulin secretion from a sulfonylurea. It is also why hypoglycaemia risk from these compounds alone is low.
Two claims get bundled together under appetite effects and they need separating. The descriptive one — this is what was observed — is usually well supported. The causal one — this is why — usually is not.
Almost every disagreement in threads like this one dissolves once you say which of the two you are making.
Post #20 answers the question as asked. The question underneath it is different.
Species differences: rodent studies show the same compounds produce effects in rodents that predict human effects reasonably well for semaglutide and tirzepatide. The track record is less clear for novel compounds with less human data.
If anyone has run this properly I would rather read that than my own guess.
I read post #22 twice before replying, because I had assumed the opposite.
Species differences in receptor pharmacology are substantial in this family, which is one reason rodent data has translated unevenly.
Building on post #24 rather than restating it.
GLP-1 receptor signalling: the GLP-1 receptor is expressed on beta cells (insulin secretion), on neurons (appetite and gastric motility), and on myocardium (contractility). Different tissues respond to the same signal in different ways.
One of those cases where knowing the mechanism does not help the decision.
Cross-reactivity and selectivity: the compounds are not perfectly selective for their target receptors. Semaglutide has some activity on other receptors; tirzepatide activates both GLP-1 and GIP with different affinities. The off-target effects are part of the overall pharmacology.
What would change my mind on appetite effects is a second dataset collected by someone with no stake in the first. Until then I hold it loosely and I would rather say so than pretend to more.
Everything in post #26 holds. The case it does not cover is the one I have.
The useful distinction on appetite effects is between what was measured and what was inferred from it. Both end up in the same sentence and only one of them has error bars.
Receptor occupancy required for a clinical effect is not the same as full occupancy, and dose-response curves flattening at the top is what you would expect from that.
None of the above is medical advice and I am not qualified to give any.
Saving this. It is the version I will quote when the question comes round again.