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Blind cavefish have evolved to be starvation resistant, constantly hungry and fat but healthy.
New research shows these fish share genetic mutations with some obese humans.
Image Credit: Nicholas Rohner
Binge-eating cavefish share gene mutation with us
Blind cavefish have adapted to annual cycles of starvation and binge-eating perhaps due to mutations in their MC4R gene. This is the same gene that is mutated in certain obese people with insatiable appetites, according to a new study led by Harvard Medical School geneticists.
The findings, published in PNAS, reveal more about how vertebrates evolved to have different metabolisms from one another and could provide insights into the relationship between human obesity and disease.
"We all know people have different metabolisms which lead to weight gain in response to differing amounts of food. Working with cavefish gives us an example in a natural setting of why and how metabolisms evolved to be different. Some of the mechanisms we see in the fish may well have implications for human metabolism and health."
Clifford Tabin, study senior author, the George Jacob and Jacqueline Hazel Leder Professor of Genetics and chair of the Department of Genetics, Harvard Medical School.
Feast and famine
As the name suggests, Mexican cavefish live in dark, isolated caves in northeastern Mexico.
In the hundreds of thousands of years since they were separated from their surface-dwelling cousins, they have adapted to their harsh environment in several ways. Without light, they gradually lost their eyes and pigmentation. With little food, they became resistant to starvation. In fact, cavefish can withstand months without sustenance by storing massive amounts of fat, and then burning it more slowly.
"These fish are very, very fat — much fatter than surface fish," explains Nicolas Rohner, a postdoctoral researcher in the Tabin lab and co-first author of the study. "Although they are active, their metabolism is slower."
Rohner works with co-first author Ariel Aspiras, a graduate student in the Tabin lab. Through controlled experiments, they found after two months without food, cavefish lost half as much weight as surface fish. After three months without food, cavefish were "totally fine," while surface fish began to die. "We think cavefish can go much longer than that, due to their immense fat reserves," added Rohner.
How did these fish become so obese in the first place? Further investigation revealed some cavefish populations evolved to have insatiable appetites. When food does become available, swept in by floods perhaps once a year, they are able to eat without limit and store as much fat as they can, which sustains them until the next feast. Also, cavefish don't sleep through times of scarcity. "That model would be similar to hibernating animals that live off stored fat for extended periods," explained Rohner. Remarkably, cavefish live long, healthy lives despite being very overweight.
Fat but fit
The research team analyzed the DNA of fish from several different caves as well as from the surrounding surface rivers to find out what genetic mutations could be driving the differences in metabolism, body weight and appetite.
Most of the cavefish had mutations in MC4R, a gene known to be regulated by leptin (an appetite-suppressing hormone) and insulin in the human brain. Lab mice without MC4R are severely obese and constantly hungry.
In people MC4R mutations, including one that is identical in some of the cavefish, are the most common single-gene cause of inherited obesity.
"MC4R is one of the key components in maintaining your energy balance," explained Aspiras. "When people try to diet or change how much they weigh, there are regulators in your brain that try to keep you at your current body weight. MC4R is one of them."
Rohner and Aspiras found that mutations appear to reduce the MC4R gene's activity in cavefish, taking the brakes off their appetite suppressor. Although this can be disastrous for people — children with MC4R mutations can't stop eating — it has proven advantageous for cavefish.
Once upon a time, it might have been advantageous for humans, too. Even before our modern obesity epidemic, humans relative to other animal species are "very fat," Rohner points out.
"There was selection for fat in our evolution, but we don't know why. Understanding how these fish became fat might eventually help us understand how we did. We have to fight against the urge to eat and drink sweet and fatty things all the time, because of our evolutionary history. Possibility we can find out why this is by using cavefish as a model system. I'm confident that one day we will find a way to resist that evolutionary urge."
Nicolas Rohner, postdoctoral researcher, Tabin laboratory, co-first author of the study.
Rohner and colleagues are convinced other genes are at play in the cavefish as the MC4R mutations don't fully explain all increases in appetite or the fish's fatty liver. They are now looking for additional mutations in cave fish which could inform the search for other human genes which influence our own metabolism and obesity.
The propensity for weight gain is detrimental to modern human health. However, under environmental conditions where nutrients are limiting, this trait can be highly adaptive. Currently, the genetic basis of population level differences in appetite control and metabolism is still largely mysterious. Here, we describe changes in metabolism that evolved in the small tetra Astyanax mexicanus as it adapted from surface rivers to the nutrient-poor environment found in caves. We identified coding mutations in melanocortin 4 receptor responsible for an increase in appetite and starvation resistance of cavefish compared with surface fish populations. These results provide important genetic insights into metabolic evolution and show that mutations in a single gene can have profound effects on multiple physiological adaptations.
Despite recent advances in the understanding of morphological evolution, the genetic underpinnings of behavioral and physiological evolution remain largely unknown. Here, we study the metabolic changes that evolved in independently derived populations of the Mexican cavefish, Astyanax mexicanus. A hallmark of cave environments is scarcity of food. Cavefish populations rely almost entirely on sporadic food input from outside of the caves. To survive under these conditions, cavefish have evolved a range of adaptations, including starvation resistance and binge eating when food becomes available. The use of these adaptive strategies differs among independently derived cave populations. Although all cavefish populations tested lose weight more slowly than their surface conspecifics during restricted rations, only a subset of cavefish populations consume more food than their surface counterparts. A candidate gene-based screen led to the identification of coding mutations in conserved residues of the melanocortin 4 receptor (MC4R) gene, contributing to the insatiable appetite found in some populations of cavefish. Intriguingly, one of the mutated residues has been shown to be linked to obesity in humans. We demonstrate that the allele results in both reduced maximal response and reduced basal activity of the receptor in vitro. We further validate in vivo that the mutated allele contributes to elevated appetite, growth, and starvation resistance. The allele appears to be fixed in cave populations in which the overeating phenotype is present. The presence of the same allele in multiple caves appears to be due to selection from standing genetic variation present in surface populations.
his work was supported by a grant from the National Institutes of Health (HD047360).
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