Blind Mexican cavefish that have adapted to annual cycles of starvation and binge-eating have mutations in the gene MC4R, 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.

The PNAS paper entitled “Melanocortin 4 receptor mutations contribute to the adaptation of cavefish to nutrient-poor conditions“ (PNAS, 2015 DOI: 10.1073/pnas.1510802112) is coauthored by Ariel C. Aspiras, Nicolas Rohner, Brian Martineau, and Clifford J. Tabin of the Harvard Medical School Department of Genetics in Boston; and Richard L. Borowsky of the New York University Department of Biology.

The researchers note that a propensity for weight gain is detrimental to modern human health, but that under certain environmental conditions where nutrients are in limited supply, this trait can be highly adaptive and beneficial.

They explain that currently, the genetic basis of population level differences in appetite control and metabolism is still largely mysterious, and in their paper they describe metabolic changes that evolved in the small Mexican tetra Astyanax mexicanus fish species as it adapted from surface rivers to the dark, nutrient-poor environment found in caves.

The coauthors identified coding mutations in the melanocortin 4 receptor responsible for an increase in appetite and starvation resistance of cavefish compared with surface fish populations, observing that the investigation’s results provide important genetic insights into metabolic evolution and show how mutations in a single gene can have profound effects on multiple physiological adaptations.

The researchers explain that despite recent advances in the understanding of morphological evolution, the genetic underpinnings of behavioral and physiological evolution remain largely unknown that their study observed metabolic changes that evolved in independently derived Astyanax mexicanus populations of the Mexican cavefish. As the name suggests, these fish live in dark, isolated caves that are located in northeastern Mexico. In the hundreds of thousands of years since they hived off from their surface-dwelling cousins, Astyanax mexicanus have adapted to the harsh cave environment in several ways. For example, without light, they gradually lost their eyes and pigmentation, and with little food available, they became resistant to starvation, and can withstand months without sustenance by storing massive amounts of fat and burning it more slowly.

“These fish are very, very fat–much fatter than surface fish,” observes Nicolas Rohner, a postdoctoral researcher in the Tabin lab at Harvard Medical School and co-first author of the PNAS study in a Harvard Medical School release authored by HMS science writer Stephanie Dutchen. “And although they are active, their metabolism is slower.”

Dr. Rohner and paper co-first author Ariel Aspiras, a graduate student in the Tabin lab, found in lab experiments that after two months without food, the cavefish lost half as much weight as surface populations. After three months, the cavefish were “totally fine,” while the surface fish began to die.

“We think the cavefish can go much longer than that, due to their immense fat reserves,” observes Dr. Rohner, who says he joined Dr. Clifford Tabin’s laboratory in order to further deepen his understanding of using genetic, genomic, and functional approaches to address interdisciplinary questions in developmental biology and evolutionary genomics. At the Tabin lab, he has largely focused on the Astyanax mexicanus cavefish model system, and in particular is currently currently working on the evolution of morphological (eye and pigmentation loss), behavioral (feeding and schooling behavior), and physiological (metabolic) traits that allowed Astyanax mexicanus to thrive in caves, as well as on the role of standing genetic variation in adaptation.

The researchers note that a characteristic of cave environments is food scarcity. Consequently, cavefish populations are obliged to rely almost entirely on sporadic food input filtering in from the environment outside of the caves they inhabit — for example swept in by floods that happen perhaps once a year. They explain that in order to survive under these conditions, the cavefish have evolved a range of adaptations, including starvation resistance and binge eating in rare occurrences when food becomes available, at which time they are able to eat without limit and store as much fat as they can to sustain them until the next influx of sustenance.

Dr. Rohner says that although the cave fish don’t sleep through times of scarcity, “this model could be similar to hibernating animals in that they live off stored fat for extended periods. However “studying hibernating bears is harder than studying fish.”

“We all know that people have different metabolisms that lead to their gaining weight under different amounts of eating,” comments the study’s senior author, Clifford Tabin , the George Jacob and Jacqueline Hazel Leder Professor of Genetics and chair of the Department of Genetics at HMS in the HMS release.

The investigators observe that use of these adaptive strategies varies among independently derived cave populations, and that 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.

They explain that candidate gene-based screen led to identification of coding mutations in conserved residues of the melanocortin 4 receptor (MC4R) gene, which is known to be regulated by leptin (an appetite-suppressing hormone) and insulin in the human brain, and the factor contributing to the insatiable appetite found in some populations of cavefish. They note that intriguingly, one of the mutated residues has been shown to be linked to obesity in humans.

“It’s one of the key components in maintaining your energy balance,” explains co-author 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.”

In the release, Ms. Dutchen notes that lab mice without MC4R are severely obese and constantly hungry. In people, MC4R mutations — including the one that is identical in some of the cavefish — are the most common single-gene cause of inherited obesity.

The scientists note that remarkably, cavefish live long, healthy lives despite being so overweight, and that the team wants to investigate further how this happens in hope that the knowledge could one day help people struggling with obesity.

Dr. Rohner and Mr. Aspiras found that the mutations appear to reduce the gene’s activity in the cavefish, deactivating their appetite suppressor. This can be disastrous in humans — children with MC4R mutations can’t stop eating — it has proven advantageous for the fish.

Dr. Rohner notes that in the past, this ability may have been advantageous for humans, too, and that even before today’s obesity epidemic, humans as a species were, relatively speaking, “very fat.”

“There was selection for that in our evolution,” he continues, “but we don’t know why. Understanding how these fish became fat might eventually help us understand how we did. That’s something that bothers me a lot — that we have to fight against this urge to eat and drink sweet and [eat] fatty things all the time and that it’s because of our evolutionary history. 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.”

Dr. Rohner and his colleagues are certain that other genes are at play in the cavefish; for instance, the MC4R mutations don’t fully explain the increase in appetite or the fish’s fatty livers, and as their investigations continue they are looking for additional mutations in the fish, which could in turn inform the search for genes that influence human metabolism and obesity.

“The work with the cavefish gives us an example in a natural setting of why and how metabolisms evolved to be different,” Dr. Tabin explains. “Some of the mechanisms we see in the fish may well have implications for human metabolism and therefore human health.”

Sources:
Harvard Medical School
PNAS
The Tabin Lab, Harvard University

Image Credits:
Harvard University
The Tabin Lab, Harvard University
Nicolas Rohner