Something strange was afoot in the Hietakangas Lab. When mutant flies were given food with an amount of sugar equivalent to what is contained in a single grape, the flies all died. When the flies were fed food that was low in sugar, in turn, they exhibited a normal growth rate.
The research team had witnessed a dramatic connection between nutrition and genetics. Now, the team is hard at work deciphering the function of genes and regulatory mechanisms that affect sugar sensitivity and how those genes and mechanisms are linked to metabolic disorders.
There’s nothing like a day out of the lab to lift researchers’ spirits. As team leader, Hietakangas is responsible for work supervision, results dissemination and funding applications, but he is also associate professor at the university. Photo by Cagri Yalgin
You can have too much of a good thing
“Through my work, I’ve observed strong interconnections between nutrition and genes. Whether a food substance is ‘good’ or ‘bad’ depends not only on quantity but also on a person’s genetic background,” explains Associate Professor Ville Hietakangas.
Hietakangas’ team is researching how genes and dietary sugars interact and how genetic factors define the safe levels of sugar consumption in animals.
The team was among the first to discover that there is a “sugar cap”, which, if exceeded, may have serious consequences. Laboratory experiments have shown that members of a certain fruit fly species that lacks a natural tendency to seek out sugary foods die when they are fed sugar.
How wild animals use sugar as a source of energy varies across species, and the differences in sugar tolerance may be surprisingly great. “We’ve shown that the so-called window of safe nutrient composition may differ considerably even between species that are genetically very similar. By comparing closely related species, we’ve observed how even a small number of mutations may induce widespread metabolic reprogramming,” Hietakangas says.
Glucose metabolites that enter a cell activate a regulatory protein complex known as Mondo-Mlx, which moves into the cell nucleus to regulate the genes that influence the metabolism. Photo by Essi Havula
Our bodies have a nutrient sensing network
Individual eating habits show clear periodical variation: sometimes we eat excessively, sometimes we barely eat at all. The functions of our body remain balanced thanks to a complex regulatory system that monitors our nutritional status.
Ville Hietakangas explains: “If an excessive amount of sugar enters a cell, your body transforms that excess sugar into fats for long-term energy storage, for instance. If, on the other hand, your body isn’t getting enough essential amino acids, it uses less of them, which results in slower muscle growth, no matter how hard you work out at the gym.”
Our cells are equipped with special sensory proteins that monitor the number of nutrient metabolites obtained from food.
“Take, for example, the sugar-sensing transcription factor Mondo-Mlx, which lies in wait for the arrival of metabolites. When metabolites enter a cell, the sensor breaks loose from its anchor and moves into the cell nucleus to activate genes. For instance, it targets fat-building genes that start to transform sugars into fats for storage. The targeted genes are partly cell-type-specific; for instance, different genes are activated in the gut than in the liver. The regulation may also target hormonal activity and thus affect our metabolism.”
The Hietakangas team has already discovered dozens of genes that influence sugar sensitivity. Some of the harmful effects of sugar are known, others are shrouded behind complicated chains of action. One clear consequence of a high-sugar diet is fatty liver disease. The team explores this link by using mouse liver cells. Another consequence is oxidative stress, which may cause structural cell damage. Sugar is an interesting research topic as it is associated with many metabolic disorders and diseases such as cancer.
Hietakangas likes to blaze his own trails and finds it rewarding to plan his research independently. He has made his study and career choices primarily based on his own interests. Photo from Ville Hietakangas’ personal albumImpact of long-term work hard to predict
Hietakangas and his team are in the final year of their four-year project grant from the Academy of Finland. By using fruit flies as a model organism, the team can screen for a great number of genes and run very controlled experiments, even if a transformation in a single factor of the regulatory system is widely reflected in the entire system.
“Different animals have very similar regulatory mechanisms when it comes to glucose metabolism. If we were able to identify an important new gene in fruit flies, we could easily pinpoint the corresponding gene in mammals,” Hietakangas says.
The team’s research comes down to basic biological knowledge, which within the overall picture is connected to many human diseases. Touching on the impact of the research project, Hietakangas says that it is impossible to predict the significance of such basic-level knowledge.
Citation counts and the number of applications are somewhat ambiguous as indicators of impact. “Such indicators provide useful comparative data, but we can’t add too much weight to a single indicator – we must look at the big picture. Citation counts can be bumped up by small-scale participation in scientific articles on popular research topics. Applications in turn often emerge in fields where the most important basic research discoveries were made many years ago.”
Funding is also needed for new initiatives such as these and for long-term efforts in fields that have received little research attention. Hietakangas would like to compare research merits with the help of transparent peer review: “A high-quality research plan speaks volumes, as do previous merits in groundbreaking observations that have significantly contributed to advancing research in a given field.”
Family time: picnicking with the kids. Photo from Ville Hietakangas’ personal album
While research may be a treasured hobby, spending time outdoors and fishing are also a great way to stay energised. Photo taken in the Lofoten islands. Photo from Ville Hietakangas’ personal album
Original Finnish text by Nina Mäki-Kihniä
This story first appeared in Finnish on www.tietysti.fi, the Academy of Finland’s website with science and research topics aimed at a general audience.