Agouti-related peptide

And it's much more complex than we used to thought.

We once had an easy, simple view that leptin-stimulated pro-opio-melanocortin suppressed its counter-regulator, AGRP, and that was all nice and simple and would tell you whether you were hungry or not.

But we now know that AGRP neurons are incredibly sensitive and they even increase at the visual appearance of food.

So these stimuli...

in this particular part of the arcuate nucleus are hugely sensitive to external stimuli like visual stimuli or the smell of food far more making that that computational aspect of the of the arcuate far more complicated than we ever thought it was because it's taking the the sort of vegetative signals if you like the leptin the propion, opium, melanocortin, those sort of simple things of how much fat do you have? How much leptin do you have? Have you got adequate calories on board? But then you're getting the moment to moment flipping of these neurons with things like vision, things like sight of food, proximity to food, smell of food, all having profound influences on those neurons.

So let me phrase it in a different way.

For the last 40 years, ever since leptin was discovered, and Jeff and others have shown how leptin works in the hypothalamus, in the NPY and AGRP neurons, at a certain area of the brain, that has fenestrated capillaries, so it's not blood-brain barrier protected.

We have studied that to death as a community because that seemed to be where everything happens.

This is certainly where also ghrelin works and where we sense a lot of signals and so on.

And using sort of genetic tools, we can see exactly what population we're looking at.

So w- so we decided to focus on the, the, the AgRP neurons, which are known to be the main neurons that drive food intake.

And we just essentially wanted to see how does that population of cells change in pregnancy.

And so for us it was a bit of...

It was a new area to work on, so we just had to spend a lot of time just technically getting up to speed with using this method to follow AgRP neurons.

And we did some basic things like that had been reported by others where you can be looking at the population of these cells, and you can give them the hormone ghrelin, which is a, a hormone from the stomach that stimulates food intake.

And when you inject that into an animal, the activity of these cells goes up.

And what do you do? You overeat.

The other side of the equation are the AgRP, the agouti-related peptide neurons, and those are signaling, "I'm hungry." So the AgRP neurons are overactive, the POMC neurons are underactive, and you're always hungry Enter GLP-1s, right? Enter Ozempic, enter semaglutide, tirzepatide

That, that fix everything.

They sort of fix everything, right? The mechanism is fascinating.