Starfish discovery may unlock new obesity treatments, scientists suggest

A new study has discovered the ancient origins of bombesin, a neurohormone crucial in regulating appetite. Nutrition Insight speaks to the lead researcher, who suggests the finding paves the way for potential applications in nutrition, such as developing treatments for obesity and managing species that impact marine food sources.

The research, published in Proceedings of the National Academy of Sciences USA, reveals that bombesin-like molecules have been controlling feeding behavior for over 500 million years. The team found bombesin in starfish, a close evolutionary relative of humans.

The evolutionary connection shows bombesin’s role in appetite regulation across diverse species, says Maurice Elphick, Ph.D., professor of Animal Physiology & Neuroscience at Queen Mary University of London, UK.

How does bombesin’s role reshape our understanding of appetite regulation?
Elphick: Our research on starfish and the work of other research groups on other invertebrates have revealed that the neurohormones that control feeding behavior are very ancient. So many of the neurohormones involved in regulating feeding and appetite in humans originated over half a billion years ago, in the common ancestor of the majority of animals on earth today. 

Bombesin joins a number of different neurohormone systems that have been shown to be involved in the regulation of feeding behavior. For example, in 2021 we published a paper reporting the discovery of a neurohormone called cholecystokinin in starfish. Cholecystokinin inhibits feeding behavior in starfish and has the same role in humans and in insects. This is an ancient neurohormone that goes right back to the common ancestor of humans, starfish, and insects, which encompasses most of the animal kingdom in terms of taxonomic diversity.

The discovery of bombesin in starfish adds to the list of neurohormones that are involved in the inhibitory regulation of feeding. But a key difference from cholecystokinin is that bombesin evolved more recently. Bombesin evolved in the branch of the animal kingdom that includes humans, other vertebrates, and starfish, but bombesin is not present in the branch of the animal kingdom that includes insects, nematode worms, mollusks (e.g., snails), and many other invertebrates. 

The discovery could lead to bombesin-inspired treatments for obesity and help manage invasive starfish impacting shellfish farms.So we have discovered a neurohormone that has a conserved role in the regulation of feeding behavior but which originated only in the branch of the animal kingdom that we humans share with starfish. This finding informs our understanding of when the neurohormones that control appetite and feeding in humans originated and acquired this function in the evolutionary history of life on Earth.

What makes starfish a key model for studying hunger-controlling neurohormones?
Elphick: If we want to understand the mechanisms by which hunger and feeding are regulated, we need to study various animal types. There has been a lot of research on appetite regulation in other invertebrates such as the fruit fly Drosophila, an insect. Drosophila is widely used as a model system for studying physiological and developmental processes, but one of the limitations of this species is that it is quite distantly related to us humans and other vertebrates. 

It is in a different branch of the animal kingdom from the branch that we humans belong to. But starfish — and other echinoderms such as sea urchins and sea cucumbers — are in the same branch of the animal kingdom as humans and other vertebrates. So the common ancestor of humans and starfish is more recent than the common ancestor of insects and humans. This means that there may be some molecules that are involved in controlling appetite that originated in the branch of the animal kingdom that we humans are part of together with starfish, but it is not present in insects and the majority of other invertebrates. 

It turns out that the neurohormone bombesin is in one such molecule. This is why studying starfish is important — it is because of their closer evolutionary relationship to humans and other vertebrates than more often studied invertebrate model species, such as Drosophila and the nematode worm C. elegans. 

Could bombesin-inspired approaches offer new obesity treatments?
Elphick: There’s actually quite a lot of evidence that the bombesin signaling system in humans and other mammals is a potential therapeutic target for the treatment of obesity and there’s a long-running program of research that’s investigating this. So, yes, bombesin-inspired drugs could offer a new approach to obesity treatment. But this is not the main focus of our research. 

Starfish, along with humans, share a common ancestor where appetite-regulating neurohormones first evolved.However, the discovery of the chemical structure of the bombesin neurohormone in starfish is useful because it can provide insight into how this molecule exerts its effects. Neurohormones like bombesin work by binding to and activating specific receptor proteins in the body. We have discovered the receptor protein that the bombesin neurohormone binds to in starfish. In ongoing research, we are investigating how this works at the atomic level. By understanding and comparing how bombesin activates its receptors in starfish and humans, it may be possible to design drugs that can be used therapeutically to mimic the action of bombesin to treat obesity

What does bombesin’s evolutionary history reveal about the origins of feeding behavior?
Elphick: The discovery of the bombesin neurohormone in starfish provides insights into the evolutionary history of hormones that control feeding behavior in humans. But what’s interesting about the feeding behavior of starfish is the way they feed. They feed by everting their stomach out of their mouth over the soft, digestible tissue of their prey, such as mussels or oysters. So they have a very different way of feeding compared to the way we humans eat. 

But what’s interesting is that although their mechanism of feeding is radically different from the way that we feed, it seems that at the molecular level, the neurohormones that are controlling feeding behavior are conserved — so the same sorts of molecules that are controlling feeding in us humans are also controlling feeding in starfish.

How might this discovery help manage invasive starfish threatening shellfish farms?
Elphick: With our knowledge of neurohormones that inhibit feeding in starfish, it may be possible to introduce chemicals into aquaculture facilities that would deter starfish from feeding on the shellfish.

We have discovered a number of different neurohormones that seem to be involved in regulating feeding behavior in starfish. We have discovered a neurohormone called asterotocin, which is related to the human hormone oxytocin, that actually promotes feeding in starfish. And we have discovered the bombesin and cholecystokinin neurohormones that inhibit feeding behavior in starfish. By identifying molecules that promote or inhibit feeding behavior in starfish, we have gained a deeper understanding of the mechanisms by which feeding is regulated in animals.

Most starfish are not in any way harmful to humans and do not present a threat to humans. But there are starfish that are a cause for concern because of the ecological impact of their feeding behavior. For example, the crown-of-thorns starfish that lives on the Great Barrier Reef off Australia is a potential concern because it feeds on coral, and expansions in the number of crown-of-thorns starfish could be one of the factors that are causing the decimation of the coral reefs.

Other starfish like to feed on shellfish like oysters, clams, and mussels, and of course humans also like to eat these. Nowadays these shellfish are not collected from the wild but they usually are grown in large numbers in special aquaculture facilities. Not surprisingly, starfish like to get into these aquaculture facilities and feed on the tasty shellfish that are there in huge numbers.