Feature: Appetite for NPY

This feature appeared in the January/February 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.

According to the Australian Bureau of Statistics’ National Health Survey for 2007-2008, a quarter of all Australians over the age of 18 are obese, meaning they have a body mass index (BMI) of 30 or above. An additional 37 per cent are overweight, meaning well over half the population are either overweight or obese. And these numbers are on the rise. The cost to the Australian economy is estimated at a staggering $58.2 billion, according to a 2008 Access Economics report. These are big numbers.

Yet obesity – and its opposite, being underweight – are not merely all in the mind; they are not just a matter of willpower. Researchers, such as Professor Herbert Herzog, Director of the Neuroscience Research Program at the Garvan Institute of Medical Research, have been uncovering the physiological and neurochemical mechanisms underpinning appetite and satiation as well as those controlling energy homeostasis in an effort to gain insight in to obesity.

The focus of Herzog’s work has been neuropeptide Y (NPY), a peptide which, he says, has been with us for a very long time. “It’s one of the most conserved peptides. There are only four amino acid changes between human and shark over 400 million years of evolution.”

With such a history, NPY is firmly entrenched in some equally ancient mechanisms controlling hunger and satiation. But that’s not all it does; NPY is known to wear a number of hats, influencing anxiety, sexual function and circadian rhythms, and untangling these disparate functions has proven to be quite a challenge.

Herzog has been specifically exploring the role of NPY in the system of appetite and satiation. He’s been looking not only at how NPY triggers hunger in the brain, but how those hunger signals are communicated to other parts of the body, and how the body sends signals back inducing satiety.

First is teasing out the various components of the NPY system. “The NPY system is quite unique in that it has three members of ligands,” says Herzog. “The first is the neuronal component, which is expressed most heavily in the hypothalamus, but also in other regions as well. When that expression is increased, such as through fasting, it strongly triggers hunger signals. So you get an enormous increase in body weight because it stimulates this very strong pathway.”

---PB---

Herzog has tinkered with this NPY pathway in experiments with mice, with some unexpected results. He found that if you overexpress NPY in the brain of some mice, and you pair feed them alongside regular mice – so they’re consuming exactly the same amount of food – the NPY mice still get fatter.

This suggests that NPY isn’t just about signalling that it’s time to eat, but it also plays a role in increasing fat accumulation. “It does this by increasing fat synthesis and fat uptake into cells and by blocking glycolysis,” he says.

One the other side of the coin is satiety. This is where two further homologous members of the NPY family come in: Peptide YY (PYY) and pancreatic polypeptide. “These are expressed mostly in the gut, the pancreas, colon and intestine,” says Herzog. “They’re released upon the ingestion of meals, and they have a couple of different functions, including intestinal motility and ion secretion. But they also send a signal back to the brain and bind to receptors to induce satiety.

“You have a system here with the same kind of family members doing two opposite things. One is stimulating the appetite pathway and the other is blocking it, inducing satiety.”

Side effects

One of the main goals of this research is to figure out ways of influencing appetite, perhaps leading to therapeutics that might help combat the health impacts of obesity. However, even with our present understanding of the role of NPY in the appetite system, it’s proven notoriously difficult to block effectively.

“Over many years myself and others have worked on targeting the brain as the major coordination centre for appetite, but it’s proven quite difficult,” says Herzog. “With many of the signals that use these pathways, if you block one, you get a slight reduction, but others compensate.”

The upshot is, there are so many overlapping pathways, that just blocking one – such as NPY – doesn’t necessarily lead to the desired result. If you think about it – given the central importance of appetite on survival – it makes sense that evolution would have furnished us with some redundancy in this area. Unfortunately, that makes it all the more difficult for us to control.

Moreover, NPY isn’t just involved in appetite, and blocking it in the brain can have adverse side effects, such as alterations in bone formation, an increase in alcohol consumption and increased seizure susceptibility. As NPY is also a stress hormone, blocking it can have unsavoury side effects, including increased anxiety.

However, there’s more than one way to make a hamburger. It occurred to Herzog that one could attempt to block the signal at its origin in the brain – as most have tried to do – or at its destination in the peripheral tissue. In a recent paper appearing in The International Journal of Obesity, Herzog and colleagues explained how they blocked the Y1 receptor – one of five that receptors involved in mediating NPY – in peripheral tissue rather than in the brain.

---PB---

The results were promising; mice with the Y1 receptor blocked in peripheral tissue were resistant to gaining fat, even on a high calorie diet. “We’ve shown here that if you only interfere with the peripheral receptors, you will receive beneficial effects on the general energy balance of the body without interfering with the appetite side,” says Herzog. “We noted that the mice lost fat, rather than muscle, yet continued to eat as normal. There were also no apparent side effects.”

This opens up the prospect of an anti-obesity medication that doesn’t come with the side effects normally associated with such drugs. However, it’s early days, and the Y1 receptor has only been blocked in specially bred and knockout mice. A drug has yet to be developed that targets the Y1 receptor with high specificity.

Them bones

Herzog has also found another interesting role for NPY: bone formation. This makes sense, says Herzog, because if you increase body weight, you’re also likely going to want to increase your bone strength to support that extra mass. “In a way, NPY matches bone mass to body weight,” says Herzog.

This opens up an interesting avenue of research linking these two seemingly disparate aspects together. In fact, they may not be that disparate at all, says Herzog. “There’s reasonable evidence that bone controls the functioning of the pancreas to some extent. You have a feedback here between obesity and bone,” he says.

This can also be seen in the functioning of mesenchymal stem cells, which can develop in to osteoblasts or adipose tissue, i.e., body fat. “So bone and fat are coming from the same kind of precursor cells,” Herzog says. “This is all somehow linked together, and I think that’s probably what the NPY system is coordinating, both in the central part of the brain, and in the local autocrine and paracrine mechanisms.”

At the Australian Neuroscience Society/Australian Physiological Society meeting being held in Sydney in February, Herzog will be giving a plenary lecture on his research and will go in to more detail about the many functions of this powerful peptide, NPY.

This feature appeared in the January/February 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.