In 2008, it was reported that a fault in a gene that is involved in metabolism and feeding behaviour – the MC4R gene, which controls the protein ‘melanocortin 4 receptor’ (MC4), which in turn binds a hormone (α-MSH) involved in regulating appetite – is faulty in many people with human obesity. Moreover, the MC4 receptor is regulated by insulin and by leptin, an appetite suppressor hormone. Evidence also points to the MC4R gene being involved in anorexia. All of which points metabolism experts to look at this crucial gene in human feeding disorders.
Now researchers at Harvard University have found that a change in MC4R helps fish that have adapted to survive in an extreme environment. Reported in Proceedings of the National Academy of Sciences, body metabolism experts have found that a change in MC4R enables Mexican cavefish to survive annual cycles of starvation and binge-eating.
Clifford Tabin, Professor of Genetics at Harvard Medical School, and a co-author of the PNAS publication, said that, "The work with the cavefish gives us an example in a natural setting of why and how metabolisms evolved to be different," he said. "Some of the mechanisms we see in the fish may well have implications for human metabolism and therefore human health."
Many thousands of years ago, Mexican cavefish (Astyanax mexicanus) evolved to survive in totally dark caves, where they live with characteristics that are not needed in their habitat, such as losing sight in their eyes. But they also evolved the ability to become resistant to starvation.
So, analysing DNA from fish from several different caves and from surface-dwelling fish all in the same area in Mexico, the researchers found that the cavefish can become grossly overweight when food is available but that they can live for long periods without food and metabolise their body fat much more efficiently than their surface-dwelling counterparts. When food is in abundance, they have insatiable appetites and can eat without limits to store as much fat as they can for the lean times.
Nicolas Rohner, one of the researchers said that, “These fish are very, very fat – much fatter than surface fish. And although they are active, their metabolism is slower.” After starving for two months, the cavefish only lost half as much weight as the surface-dwelling fish, and after three months the cavefish were “totally fine” while the surface-dwellers were beginning to die. "This model could be similar to hibernating animals in that they live off stored fat for extended periods," said Rohner.
Comparing these results with human children with MC4R mutations – who are constantly hungry and can't stop eating – the researchers were excited to see that although the mutations appear to reduce the gene's activity in the cavefish, taking the brakes off their appetite suppressor – which can be disastrous for modern people – it has been an evolutionary advantage for the fish.
Rohner again: "Understanding how these fish became fat might eventually help us understand how we did … we have to fight against this urge to eat and drink sweet and fatty things all the time and that it's because of our evolutionary history," he added. "The possibility that we can find out why that is, perhaps by using these cavefish as a model system, makes me confident that one day we will find a way to resist that urge."
Bob is a freelance science writer and publisher