Liver hormone stops "sweet tooth"

It may be your liver that keeps you away from sweets overload this holiday season. New research describes a breakthrough in understanding sugar appetite, the so-called “sweet tooth”. 

The study, co-directed by Assistant Professor Matthew Gillum from Novo Nordisk Foundation Center for Basic Metabolic Research (University of Copenhagen) and Assistant Professor Matthew Potthoff (University of Iowa), shows that a hormone produced by the liver suppresses intake of sugar. The hormone, fibroblast growth factor 21 (FGF21), is the first identified liver-derived hormone that controls appetite.

The recent discovery showing that the liver reduces sugar intake by producing FGF21 has been published in  24 December 2015 issue of  the scientific journal Cell Metabolism.

Inspiration
Researchers followed up on a human genome-wide association study which found relations between certain mutations and people’s intake of specific macronutrients (fat, protein, carbohydrates). Since two of these mutations were located near the FGF21 gene, the scientists were inspired to investigate how FGF21 might affect appetite. 

“Even though there has been a lot of research on FGF21, its physiological function is still a bit mysterious,” says co-senior author Matthew Gillum and continues, “And our research suggests a function that has not been described before but fits with the human genetic data showing FGF21 variants may influence food preferences somehow.”

Regulating sugar intake through FGF21
“To find out how exactly liver can regulate sugar intake through FGF21, we made use of several mouse models,” says Stephanie von Holstein-Rathlou, co-first author and Mater's thesis student at Section for Metabolic Imaging and Liver Metabolism at the Novo Nordisk Foundation Center for Basic Metabolic Research.

“In normal mice, we injected FGF21 and gave the mice a choice between a normal diet and a sugar-enriched diet.” What the researchers saw was a surprise – the mice stopped eating sugar within the first two hours after injection and ate seven times less sugar than normally. Some days after the last injection, the mice started eating more sugar again.

The second investigation was conducted by using genetically modified mice that either do not produce FGF21 at all or produce a lot of FGF21 (1000 times more than normal mice). Similarly to the first experiment with the normal mice, the investigators gave them a choice between two diets: a normal and a sugar-enriched one. The researchers were able to observe that the mice that do not produce FGF21 at all eat twice as much, whereas the mice that produce a lot of FGF21 eat less sugar.

Fondness for sweets decreased by FGF21
“Based on these studies, and more, we can conclude that FGF21 decreases appetite and intake of sugar,” says Stephanie von Holstein-Rathlou. However, as the study shows, FGF21 does not reduce intake of all sugars equally efficiently: sucrose (a common, naturally occurring carbohydrate found in e.g. cane or beet sugar), fructose (fruit sugar), and glucose (grape sugar) intake all seem to be decreased, however, sucrose most of the three. As to the intake of artificial sweeteners such as sucralose, it has been also reduced according to the study.

“We never imagined that a circulating, liver-derived factor would exist whose function is to control sweet appetite,” says Matthew Gillum. “We are very excited about investigating this hormonal pathway further.”

This research opens up new avenues for potential investigation on more hormones like FGF21 – the hormones that exist to regulate appetite for specific macronutrients. Investigating further on this matter could be quite beneficial for improving diet quality (e.g. preventing junk food consumption). Used therapeutically, the study could potentially help alleviate the diabetes and obesity pandemic by decreasing people’s preference for sugar and reducing their sugar appetite and intake.

The study is a result of collaborations between researchers from:
• Section for Metabolic Imaging and Liver Metabolism
• Section for Metabolic Receptology and Enteroendocrinology, the Novo Nordisk Foundation Center for Basic Metabolic Research
• Department of Biomedical Sciences
• Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, 2200 Copenhagen, Denmark
• Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
• Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO 80045, USA
• School of Sport, Exercise, and Rehabilitation Sciences, and Institute of Metabolism and Systems Research, University of Birmingham, UK
• Department of Pharmacology
• Department of Psychiatry
• Department of Neurology
• Department of Anatomy and Cell Biology
• Fraternal Order of Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA

Read the whole study (http://dx.doi.org/10.1016/j.cmet.2015.12.003) in the December issue of Cell Metabolism.