Double action weight loss drug reawakens appetite signals

Weight-loss jabs - like Ozempic and Mounjaro - have been in the news a lot lately. They work mainly by simulating the action of one of the body’s signals called GLP-1, which shoots up when we eat. But there’s also another important signal in the form of a hormone called “leptin”, which is released by fat tissue in increasing amounts as we gain weight. And the brain uses it to regulate eating behaviour, except when we start to put on too much weight. Now the pharmaceutical company Novo Nordisk have developed a new molecule, one end of which looks like leptin, and the other end resembling GLP-1. This seems to be able to trigger a population of appetite-regulating cells in the brain, and sensitise, or even re-sensitise them to leptin, significantly boosting rates of weight loss in experimental mice. Randy Seeley is the director of the Michigan Nutrition Obesity Research Center where he’s been working on this potential new drug. He told me what he’s found…

Randy - Leptin is released from your fat tissue and it essentially tells your brain how many stored calories you have in your body. Your brain uses that information to be able to maintain your body weight, to figure out how much you should eat and how much you should burn. What's interesting is, when it was first discovered, people thought, 'Oh my gosh. This is going to be a great therapy for individuals with obesity. It turned out not to be true. The reason it wasn't true is that it turns out that individuals with obesity aren't leptin deficient. That is, they don't have low leptin levels, rather they have high leptin levels and they seem to be resistant to the ability of that leptin to be able to give them information about whether they have sufficient stored calories. So let me give you an example. If you took a lean mouse and you gave it leptin, you're essentially tricking that animal into thinking that it has more stored calories and the animal does something pretty sensible in reply, it stops eating. But when you do that in a mouse that's been made obese, it turns out it doesn't respond to leptin. So the whole trick of this is trying to understand, is there a way to still use leptin from a therapeutical perspective that might be part of the armamentarium that we use to treat individuals with obesity

Chris - In overweight situations, then, it's as though the brain has become deaf to the signal of leptin and you are asking, can we restore hearing to that part of the brain? It's like a hearing aid for the brain. Can we resensitise it so it does respond to the leptin signal which says, you have too many calories on board, you need to lose some weight.

Randy - Exactly. How do we resensitise the brain? How do we turn that hearing back on in a way so that it can listen to both their own leptin and the leptin that comes in the form of this particular molecule?

Chris - So you think that you've got a drug here which can do that. How does it work?

Randy - We identified a set of neurons in a specific part of the brain called the hypothalamus, and those neurons express both the receptor for GLP-1 and the leptin receptor. We verified that that's not just true in mice, but it was true in non-human primates as well, that there's this set of neurons. And then we used a variety of genetic tricks to either add or remove leptin receptors from that area of the brain, in these cells that also express the GLP-1 receptor. It turns out these neurons are both necessary and sufficient for the actions of this particular drug.

Chris - Why should hitting the neurons with this agent that stimulates both the leptin signal and the GLP-1 signal at the same time be an effective strategy to make the cells more sensitive to this fat signal, leptin?

Randy - You're asking a really good question. What we know is that when we add this GLP-1 component, we get a response that you wouldn't get with leptin alone. There are two ways to think about this. One is, if we prime the animal to begin losing weight with the GLP-1 side of the molecule, we now get the system cranked back up and turned back on so that it can start hearing the leptin side. It doesn't matter what you would do. You could do lots of different things and maybe they would all be effective at making leptin able to hear the signal that leptin brings. The other side of it really has to do with these particular neurons. The idea that we're hitting the GLP-1 receptor, turning on that signalling cascade in these neurons that restores their ability to be able to hear the leptin signal. That's the side that we favour. But again, it's pretty hard to prove between those two particular hypotheses.

Chris - I suppose that if you view the weight loss that would arise from this as two phases, because normally if someone loses weight, then the amount of leptin would drop. So they would lose whatever drive they were getting to lose more weight because they're losing leptin. But if you have a molecule that seems to fool the brain into thinking the level is staying high and it stays sensitive to it, you're going to reinforce the weight loss for longer. So in theory, you could actually have a much more effective pattern of weight loss.

Randy - That's what we show. One of the things that Novo cleverly did was to make versions of the molecule that only had one side or the other, but looked similar. We were able to use those kinds of research tools to be able to ask what happens when you only push on one side or the other. And the answer is, you don't get as much response as if you are able to push on both of them at the same time.

Chris - How much response do you get? We know when people use these agents, when people have done trials with the existing GLP-1 agonist, drugs like Ozempic, for example, Mounjaro, that kind of thing, we know that translates over the period of treatment to a weight loss of between 10 and 15% of body weight. So if you bring your new double acting drug to bear, what sort of levels do you think you would get with this?

Randy - I don't think we can know from this study. We didn't do the kinds of comparisons that would allow you to be able to directly compare molecules like tirzepatide or semaglutide. As you can imagine, it's not a trivial thing to be able to do. Mice are different and particularly they're different in how they metabolise a drug, that is, how long the drug lasts. And so trying to do those kinds of comparisons turns out to be really tricky. I think it's going to take some time to tell whether a molecule like this one could be as effective or more effective. We just don't know today.