In a study published in Cell Metabolism, research indicated the liver hormone FGF21, or fibroblast growth factor 21, to be responsible for the brain’s actions to increase water intake to prevent dehydration.

Researchers from the University of Texas Southwestern Medical Center (UT Southwestern) have been studying FGF21 for a long time, with earlier research pointing out the hormone’s ability to act using the brain’s reward pathway to control the need for sugar and alcohol in favor of drinking water.

“We knew that exposure to alcohol or sugar turns on production of FGF21 in the liver. What we now show is that this hormone then travels in the blood to a specific part of the brain, the hypothalamus, to stimulate thirst, thereby preventing dehydration,” explained Dr. Steven Kliewer, a professor at UT Southwestern. “Unexpectedly, FGF21 works through a new pathway that is independent of the classical renin-angiotensin-aldosterone thirst pathway in the kidneys.”

In the study, the team discovered that FGF21 regulated hydration in response to nutrient stress. Using both healthy mice and those that were mutated to be genetically unable to produce FGF21, they discovered that while both mice were able to drink similar amounts of water after a standard diet, the mutated mice were unable to produce FGF21 after they were subjected to a high-fat/low-carbohydrate ketogenic diet. According to researchers, this established the role of the hormone in the signaling pathway.

The team also looked at how FGF21 responds in humans in a clinical trial at the Medical University of Graz in Austria. In the trial, a total of 21 participants were assigned to drink either a mixture of alcohol and juice or a mixture of juice alone. After drinking, researchers measured their FGF21 levels in their blood in hourly intervals over four hours. Based on the results, FGF21 peaked in response to alcohol two hours after consumption, then fell afterward.

“This suggests that FGF21 might someday be used as a drug to limit alcohol consumption and protect against its effects in people,” UT Southwestern’s Dr. David Mangelsdorf added. “[These] findings also suggest that FGF21 is regulated the same way in humans as in mice and that the process involves the expression and activation of certain proteins in the brain.”

The results of the study, the researchers said, could change how feeding behavior is studied. Currently, the focus of behavior has been on metabolic behavior, instead of hydration.

“To put this in context, we always look at food intake, and the metabolic field has spent comparatively little time studying water intake,” Kliewer added. “This study suggests that we should think more about hydration and how it might contribute to metabolism.” 

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