The holiday season inevitably brings us temptation after temptation in a variety of forms, none more familiar than those sugary treats. Though, while sugar cravings are common, the physiological cause of that sweet tooth is less well understood. A new American-Danish study has pinpointed the hormone responsible for reining in that craving and published research that could lead to an improved diet and so help patients who are diabetic or obese.
A study using mice led by a team at the University of Iowa (UI) shows that a hormone produced by the liver — known as fibroblast growth factor 21 (FGF21) — suppresses the common craving for simple sugars many of us would recognize all too well. And, as we know, those sugars can be sneaking in disguised as the carbs in processed food — as we consume carbohydrates, our bodies break down the simple sugars. FGF21 is produced in response to high carbohydrate levels, entering the bloodstream and sending a signal to the brain to suppress the hankering for even more sweet things.
Previous research has already explained how certain hormones affect appetite. The hormones with which scientists were familiar, however, do not regulate any specific macronutrient (carbohydrates, proteins and fats) and are known to be produced by organs other than the liver. FGF21 is different. "This is the first liver-derived hormone we know that regulates sugar intake specifically," says Matthew Potthoff from UI's Carver College of Medicine. Potthoff is co-senior author of the paper along with Professor Matthew Gillum of Denmark's University of Copenhagen. Their joint paper is published online in the journal Cell Metabolism.
The new research is based on studies of the human genome where researchers looked at associations between certain DNA mutations and how they relate to the intake of specific macronutrients. The team noticed that two of the mutations were located near the gene that controls FGF21, so they decided to try to identify the role this hormone has in regulating macronutrient preference. "We've known for a while that FGF21 can enhance insulin sensitivity," says Lucas BonDurant, a fellow researcher working on the project. "Now, there's this dimension where FGF21 can help people who might not be able to sense when they've had enough sugar, which may contribute to diabetes."
BonDurant and his colleagues used mice to begin to investigate the specific effects of FGF21. Giving regular healthy mice a small injection of the hormone, they then allowed them a choice between a normal diet and one that was sugar-enriched. They noticed that, although the mice didn't completely stop eating sugar, they actually ate seven times less than normal. The team also took genetically modified mice that either didn't produce FGF21 at all or produced a lot of FGF21 — more than 500 times that of normal mice — and gave them the same choice between the same two diets as the normal mice. While the mice that didn't produce FGF21 at all ate more sugar, the mice that produced a lot of FGF21 ate less sugar.
Based on their results, the team concluded that FGF21 fundamentally affects the appetite for and intake of sugar. However, they say, the effect of FGF21 is not the same for the intake of all sugars — sucrose, fructose and glucose — and doesn't impact the intake of complex carbohydrates. Though the three kinds of sugar are related — and certainly taste very similar to us — they have different structures and the body processes them in different ways. Fructose (the sugar we get mainly from fruit and vegetables), for example, does not trigger the release of insulin but is metabolized by fructokinase, an enzyme produced by the liver.
While BonDurant's team showed that FGF21 sends the appropriate sugar-limiting signals to the brain, they admit additional work is necessary to identify precisely which neural pathways regulate FGF21's ability to manage macronutrient preference. Researchers at UI think the key may be in the hypothalamus — this is the section of the brain responsible for regulating feeding behavior and energy homeostasis, the body's capacity to regulate its own systems to maintain overall stability. "In addition to identifying these neural pathways, we would like to see if additional hormones exist to regulate appetite for specific macronutrients like fat and protein, comparable to the effects of FGF21 on carbohydrate intake," Potthoff says.