image: Cravings for sweet foods are common, yet the mechanisms that influence the ''sweet tooth'' are not well-defined. This visual abstract depicts how in response to carbohydrate intake, the liver produces FGF21 to selectively suppress sugar appetite by acting on the PVN of the hypothalamus. view more
Credit: von Holstein-Rathlou and BonDurant et al/Cell Metabolism 2015
It may be your liver (and not your better judgement) that keeps you away from excess sweets this holiday season. Two independent research groups have found the first evidence of a liver-derived hormone that specifically regulates intake of sugars and alcohol in mice. One of the studies also found that the same hormone suppresses the consumption of sweets in primates.
"A lot of work has examined the central mechanisms regulating sugar-seeking behavior, but the post-ingestive mechanisms regulating sugar appetite are poorly understood," says Matthew Potthoff of the University of Iowa, a senior author on one of the papers.
"We never imagined that a circulating, liver-derived factor would exist whose function is to control sweet appetite, says his co-senior author Matthew Gillum of the University of Copenhagen. "We are very excited about investigating this hormonal pathway further."
The studies, together with human genetics studies linking the hormone--called FGF21 (or fibroblast growth factor 21)--to nutrient preference, "show that FGF21 can exert powerful effects on behavior by acting on the central nervous system, including in humans," says Steven A. Kliewer of University of Texas Southwestern Medical Center, a senior author on the other paper.
He adds one note of caution: "While at first blush it would seem that this FGF21-regulated pathway could be a panacea for suppressing sugar and alcohol consumption, it's important to keep in mind that these reward behaviors are closely tied to mood, and so additional studies to determine if FGF21 causes depression are certainly warranted."
The study from the lab of Kliewer and David J. Mangelsdorf at UT Southwestern and collaborators at Pfizer looked at FGF21 in both mice and monkeys. He says that while many signaling pathways in the central nervous systems are known to influence sweet and alcohol preference, this is the first liver-derived hormone found to have these effects. He was also struck by how powerfully FGF21 could suppress appetite, as a single dose could cause a monkey to almost immediately lose interest in sweet water.
But how is FGF21 working? In the other study, led by Potthoff and Gillum, they showed that, in mice, the liver produces FGF21 in response to sugar intake. FGF21 then enters the bloodstream and selectively suppresses sugar appetite by acting on the hypothalamus, a part of the brain that regulates food intake and energy homeostasis.
"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. "If so, how do those signals intertwine to regulate the neural sensing of different macronutrients?"
Studies from over 50 years ago suggested that the liver was an important regulator of food intake and preference. Previous work has also shown that FGF21 is derived primarily from the liver, and that variations in the FGF21 gene sequence are associated with changes in macronutrient preference in humans. All of this together led Potthoff and Gillum to evaluate the role of FGF21 in regulating food preference.
We can only speculate why FGF21 exists in animals: Does it improve diet quality, preventing junk food consumption? Or, since sugar can ferment into ethanol, does it help the liver protect itself from excess alcohol? Whatever its origin, its ability to prevent overconsumption of sugar could be harnessed therapeutically upon further investigation in humans and could help explain why analogs of FGF21 are currently undergoing clinical evaluation for the treatment of obesity and type 2 diabetes.
Both groups agree that more work is needed, but the studies add to the growing evidence that--from gut microbes to our organs--controlling appetite is a whole-body affair.
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Paper 1: Cell Metabolism, von Holstein-Rathlou and BonDurant et al: "FGF21 Mediates Endocrine Control of Simple Sugar Intake and Sweet Taste Preference by the Liver" http://dx.doi.org/10.1016/j.cmet.2015.12.003
The study was funded in part by grants from the American Diabetes Association, the National Institutes of Health, the Edward Mallinckrodt Jr. Foundation, the University of Iowa Fraternal Order of Eagles Diabetes Research Center, and the Novo Nordisk Foundation Center for Basic Metabolic Research.
Paper 2: Cell Metabolism, Talukdar and Owen et al: "FGF21 Regulates Sweet and Alcohol Preference" http://dx.doi.org/10.1016/j.cmet.2015.12.008
This work was supported by the National Institutes of Health, the Robert A. Welch Foundation, the Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society, the Ford Foundation Fellowship, the German National Science Foundation, and the Howard Hughes Medical Institute.
Cell Metabolism (@Cell_Metabolism), published by Cell Press, is a monthly journal that publishes reports of novel results in metabolic biology, from molecular and cellular biology to translational studies. The journal aims to highlight work addressing the molecular mechanisms underlying physiology and homeostasis in health and disease. For more information, please visit http://www.cell.com/cell-metabolism. To receive media alerts for Cell Press journals, contact press@cell.com.
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