Liver Stress Hormone Talks to the Brain to Reduce Alcohol and Sugar Preference

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Endocrinology researchers already knew that a stress hormone secreted in the liver—fibroblast growth factor 21, or FGF21—helps regulate metabolism in humans and mice. Now, a new study published by researchers at UT Southwestern Medical Center in Cell Metabolism is the first to discover that FGF21 communicates directly with the brain via the brain’s reward pathway to control preferences for, and amounts of, sugar and alcohol consumption in mice—and potentially humans. This could lead to new drugs to treat diabetes, alcoholism, and other forms of addiction. 

Though the new study was conducted on mice, co-senior author Steven Kliewer, a professor of molecular biology and pharmacology at UT Southwestern, tells mental_floss: “Our springboard for this study was human studies. One of the nice things about this is that we already have evidence of human relevance, not just a rodent phenomenon.” 

Kliewer runs a joint laboratory with David Mangelsdorf, with whom he has done four total studies on FGF21. Two studies published in Nature Medicine in 2013 showed FGF21’s ability to regulate metabolism, circadian behavior, and female reproduction. In 2014, their study published in Cell Metabolism showed that FGF21 can cause weight loss. 

Kliewer and Mangelsdorf knew the liver releases FGF21 in response to a variety of stresses, such as marked changes in metabolic and environmental stresses that accompany starvation or exposure to extreme cold, but, Kliewer says, “We hadn’t anticipated that there would be this endocrine loop where the liver communicates with the brain to regulate nutrient preference.”

FGF21 sends the message “too much” to the brain when it is consuming sugar or alcohol, “but obviously it’s not enough to stop overconsumption in the long run,” Kliewer says. At least, not yet. He believes that the FGF21 pathway “could be very powerful to exploit in terms of developing drugs to treat addiction.”

The researchers demonstrated that mice with elevated levels of FGF21 showed a reduced preference for either sweetener- or ethanol-laced water. The mice were given “free access” to food and a choice between two water bottles in their cages. In the first experiment, one of the bottles contained only water and the other contained sweetened water. They repeated the experiment with two bottles of water and one with concentrations of ethanol. Then they measured how much the mice drank from each bottle.  

They were surprised to find that the FGF21 mice showed reduced interest in either the sweetened or the ethanol water, and preferred plain water. Furthermore, they showed that FGF21 was responsible for the decreased preference for sweet and alcohol in the brain, accompanied by a decrease in dopamine levels. “We found that FGF21 affects neurotransmitter dopamine levels, which is important for lots of reward behaviors, it’s a global reward regulator,” Kleiwer says.

FGF21 requires a co-receptor, β-Klotho, to function. To confirm that FGF21 acts along the brain’s reward pathway, they increased its levels in mice that had been genetically modified to be unable to produce β-Klotho and found the taste preference effect disappeared.

From here they hope to understand the molecular pathways of FGF21 better for its drug potential in the treatment of addiction, which will require more study due to its known side effects. “We already know that it causes some bone loss when it’s taken long term at high levels,” says Kliewer. “And any time you start messing around with reward behaviors, you have to worry about depression.”

Kliewer says that the questions driving the next phase of research will include: “What is the reason the liver does this [secretes FGF21 along the brain’s reward pathway]? Under what conditions naturally? And can the levels of FGF21 be increased in humans?”

He cautions that it's a long process to bring research findings into clinical settings. “This is exciting biology and has promise, but … people have to take this [finding] with a grain of salt.”