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Diet and lifestyle

Natural hormone can get you to choose salad instead of candy

Researchers made a startling discovery a few years ago: the liver, which secretes a hormone called FGF21, controls people’s sweet tooth. FGF21 strongly suppresses our desire to consume sugar and alcohol. However, translating this knowledge into medicine that can treat overweight people with sugar cravings requires that researchers understand why evolution has provided us with a hormone that inhibits the appetite for sugary sources of energy. Evidence suggests that FGF21 resulted from our ancestors’ consumption of fermented fruit and alcohol.

The epic internal battle people experience between eating a healthy salad versus a sweet cake is well known, and the cake is increasingly winning for now. Researchers have therefore focused on determining why we choose unhealthy food rather than healthy food. Glands, fat cells or the digestive system secrete most of the known hormones that regulate hunger and appetite. The discovery that the liver secretes fibroblast growth factor 21 (FGF21), a hormone that very specifically regulates our desire to consume sugar and alcohol, was therefore both surprising and promising.

“Increasing the concentration of FGF21 in mice halves their consumption of sugar, and removing it entirely makes the mice almost uninhibited in ingesting sugar and alcohol. We therefore believe that FGF21 has evolved to protect our ancestors from consuming excessive amounts of fermented fruit and alcohol. Now we hope that FGF21 can help people in combating overweight and obesity if we can develop it into something that can inhibit the craving for sugar,” explains Matthew P. Gillum, Associate Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Consume twice as much sugar if the gene is missing

Since research discovered the remarkable function of FGF21 in 2016, many studies have been carried out to understand how it works and especially whether it has the same effects on people as on rodents. The researchers have now collated all these results and knowledge into a review article in the Journal of Physiology.

“In 2016, research showed that FGF21 selectively inhibits mice’s consumption of sugar and especially alcohol, which develops when sugar-laden food such as fruit ferments. But FGF21 does not affect their intake of fat, protein or more complex carbohydrates. Since then, researchers have demonstrated the same effect among people, especially for consuming alcohol.”

Genetic studies have even revealed that the quantity of candy and alcohol people consume varies with changes in the gene encoding FGF21, which suggests that the natural variation in the amount of FGF21 each person secretes explains differences in people’s appetite for sugar and the fermented products of sugar.

“We still do not know exactly which changes have which effects, but we can artificially reduce mice’s appetite for sugar – either by injecting FGF21 into the bloodstream or by genetically overexpressing the gene encoding for it. If we remove the gene completely from these mice, then they consume about twice as much sugar and alcohol as normal.”

Defence against fermented fruit

The latest research emphasizes that improving the understanding of how hormones interact in the body is crucial for solving the growing challenge in high-income countries related to the numerous complications the obesity epidemic causes such as type 2 diabetes, non-alcoholic steatohepatitis, cardiovascular disease and cancer.

“The big question we need to answer to meet this challenge is how these hormones interact with the brain. For example, how do the strong signals we get from our taste buds when we eat sugar interact with how the brain otherwise realizes which types of food provide energy and the building blocks the body needs? It is quite obvious that evolution deceives us in influencing the food we eat now compared with what our ancestors ate back then.”

One of the researcher’s theories about the function of FGF21 is based on how the world was once. The liver seems to have a negative feedback mechanism so that consuming sugar or alcohol increases the secretion of FGF21 shortly afterwards.

“We believe that FGF21 is the body’s attempt to protect against the toxic effects on the liver resulting from, for example, consuming excessive fermented fruit, which was an important food source for our ancestors. Presumably, therefore, people’s livers respond to excessive intake of sugar and alcohol by producing a hormone that reduces appetite for alcohol and sugar.”

It is still too early to confirm this theory, but the researchers are busy investigating how differences in the concentration of FGF21 influences people’s appetite. In addition, the researchers plan to repeat the experiments that have previously been done on mice but using the alcohol-consuming vervet monkeys from Saint Kitts in the Caribbean.

“Of course, the ultimate question is why we still consume so much sugar despite producing FGF21, which should inhibit our appetite for sugar. Does this result from genetic changes that reduce the secretion of FGF21or from other factors in the interaction between hormones? If we succeed in finding these connections, we can probably also find a way to influence the balance so that we learn to resist the temptations of sugar – and thereby may increase our appetite for healthier food and avoid becoming overweight and developing fatty liver.”

FGF21: an endocrine inhibitor of sugar and alcohol appetite” has been published in the Journal of Physiology. Matthew P. Gillum is an Associate Professor at the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Matthew Paul Gillum
Associate professor
The Gillum Group characterizes hormones and metabolites generated via the gut, gut microbiota, and liver that govern host metabolism and appetite. We identify the receptors and cellular targets through which they exert their beneficial or detrimental effects with the goal of identifying novel therapeutic possibilities. The overarching hypothesis is that the liver, gut, and gut microbiome affects host metabolism through the production of key metabolites and hormones which enter the body to act on target proteins or receptors expressed in endocrine and metabolic organs of the host. The current challenge is to move beyond descriptive studies and identify the mechanism by which the liver, gut, and gut microbiota contribute to host metabolism, appetite and the development of metabolic disease. The Gillum Group characterizes identified metabolites generated via the gut microbiota, gut, and liver that affect host metabolism and appetite. We identify the receptors and cellular targets through which they exert their beneficial or detrimental effects. Identifying such metabolite receptor pairs may provide novel therapeutic possibilities by either targeting metabolite synthesis or developing receptor agonists/antagonists. We anticipate to find several unidentified microbial metabolites that could affect host metabolism, as well as hepatic factors that regulate appetite.