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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.”

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Scientists Think They Know What Causes Trypophobia
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Picture a boat hull covered with barnacles, a dried lotus seed pod, milk bubbles on a latte, or a honeycomb. Images of these objects are harmless—unless you're one of the millions of people suffering from trypophobia. Then they're likely to induce intense disgust, nausea, and fear, and make your skin crawl.

Coined fairly recently, the term trypophobia describes the fear of clusters of holes. The phobia isn’t recognized by the Diagnostic and Statistical Manual of Mental Disorders, but its visibility on the internet suggests that for many, it’s very real. Now, scientists in the UK think they've pinpointed the evolutionary mechanism behind the reaction.

Tom Kupfer of the University of Kent and An T. D. Le of the University of Essex shared their findings in the journal Cognition and Emotion. According to their research, trypophobia evolved as a way to avoid infectious disease. Thousands of years ago, if you saw a person covered in boils or a body covered in flies, a natural aversion to the sight would have helped you avoid catching whatever they had.

But being disgusted by skin riddled with pathogens or parasites alone doesn't mean you're trypophobic; after all, keeping your distance from potential infection is smart. But trypophobia seems to misplace that reaction, as the authors write: "Trypophobia may be an exaggerated and overgeneralized version of this normally adaptive response."

Lotus pod.
Lotus seed pods are a common trigger of trypophobia.

This explanation is not entirely new, but until now little research has been done into whether it's accurate. To test their hypothesis, the scientists recruited 376 self-described trypophobes from online forums, and another 304 college students who didn't claim to have the affliction. Both groups were shown two sets of images: The first depicted clusters of circle-shaped marks on animals and human body parts (the "disease-relevant cluster images"); the second showed clusters of holes on inanimate objects like bricks and flower pods ("disease-irrelevant cluster images"). While both groups reported feeling repulsed by the first collection of photographs, only the trypophobes felt the same about the pictures that had nothing to do with infection.

Another takeaway from the study is that trypophobia is more related to sensations of disgust than fear. This sets it apart from more common phobias like arachnophobia (fear of spiders) or acrophobia (fear of heights). And you don't have to be trypophobic to be disgusted by a video of Suriname toadlets being born through holes in their mother's back. We can all be grossed out by that.

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Live Smarter
Researchers Say You’re Exercising More Than You Think
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They say a journey of a thousand miles starts with a single step. If the thought of a thousand-mile journey makes you tired, we've got some great news for you: You've probably already completed one.* A new study published in the journal Health Psychology [PDF] finds that people underestimate the amount of exercise they're getting—and that this underestimation could be harmful.

Psychologists at Stanford University pulled data on 61,141 American adults from two huge studies conducted in the 1990s and the early 2000s: the National Health Interview Survey and the National Health and Nutrition Examination Survey. Participants answered questionnaires about their lifestyles, health, and exercise habits, and some wore accelerometers to track their movement. Everybody was asked one key question: "Would you say that you are physically more active, less active, or about as active as other persons your age?"

The researchers then tapped into the National Death Index through 2011 to find out which of the participants were still alive 10 to 20 years later.

Combining these three studies yielded two interesting facts. First, that many participants believed themselves to be less active than they actually were. Second, and more surprisingly, they found that people who rated themselves as "less active" were more likely to die—even when their actual activity rates told a different story. The reverse was also true: People who overestimated their exercise had lower mortality rates.

There are many reasons this could be the case. Depression and other mental illnesses can certainly influence both our self-perception and our overall health. The researchers attempted to control for this variable by checking participants' stress levels and asking if they'd seen a mental health professional in the last year. But not everybody who needs help can get it, and many people could have slipped through the cracks.

Paper authors Octavia Zahrt and Alia Crum have a different hypothesis. They say our beliefs about exercise could actually affect our risk of death. "Placebo effects are very robust in medicine," Crum said in a statement. "It is only logical to expect that they would play a role in shaping the benefits of behavioral health as well."

The data suggest that our ideas about exercise and exercise itself are two very different things. If all your friends are marathoners and mountain climbers, you might feel like a sloth—even if you regularly spend your lunch hour in yoga class.

Crum and Zahrt say we could all benefit from relaxing our definition of "exercise."

"Many people think that the only healthy physical activity is vigorous exercise in a gym or on a track," Zahrt told Mental Floss in an email. "They underestimate the importance of just walking to the store, taking the stairs, cleaning the house, or carrying the kids."
*The average American takes about 5000 steps per day, or roughly 2.5 miles. At that pace, it would take just a little over a year to walk 1000 miles.


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