Sense of satisfaction generated by alcohol consumption successfully sustained to guide reduced drinking

Why do people drink too much alcohol? Professor Tsutomu Sasaki, Assistant Professor Sho Matsui, and their colleagues from the Graduate School of Agriculture at Kyoto University, in collaboration with Professor Takatoshi Hikida and others from the Institute for Protein Research at the University of Osaka and Peking University, have elucidated that when alcohol is consumed, fibroblast growth factor 21 (FGF21) is secreted from the liver, activating oxytocin-positive neurons in the brain; the continued activation of dopamine neurons generates a sense of satisfaction, which extends the interval between drinking episodes. It was found that in alcohol dependence model mice, this function was impaired and that reduced drinking could be achieved by mixing FGF21-inducing components into food or alcohol. This is expected to lead to the development of new methods for reducing alcohol consumption. The research was published in the Proceedings of the National Academy of Sciences.

Excessive drinking is the greatest risk factor for death and disability in people under 49 years of age, and of the 2.4 billion people who drink alcohol worldwide, 1.3 billion consume amounts that are harmful to health. In Japan, approximately 20% of the drinking population (about 14 million people) consume amounts of alcohol that are harmful to health, and approximately 1.07 million people are estimated to have alcohol dependence. The WHO adopted the "Global Strategy to Reduce the Harmful Use of Alcohol" in 2010, and Japan also enacted the Basic Act on Measures Against Alcohol-related Harm in 2013. The Ministry of Health, Labour and Welfare published guidelines on health-conscious drinking in 2024.

However, some people drink too much even though they know it is bad for their health. For alcohol dependence, psychological support is said to be more effective than medication, and there are no effective means to reduce excessive drinking. So why do people drink too much alcohol?

The research group hypothesized that, unlike the conscious feeling of intoxication, drinking brings about a sense of satisfaction at a level below conscious awareness, and that when the function that generates this sense of satisfaction declines, people drink more. In that case, it may be possible to reduce drinking by supplementing the sense of satisfaction with components other than alcohol, and a new strategy can be presented to reduce alcohol consumption by providing alternative pleasures instead of forcing abstinence.

The research group revealed through genetic modification and brain surgery in mice that when alcohol is consumed, the hormone FGF21 secreted from the liver activates oxytocin-positive neurons in the brain and sustains the activity of dopamine neurons in the brain for a long time, thereby generating a feeling of being "satisfied" (sense of satisfaction).

A new mouse model mimicking alcohol dependence was created. In this mouse model, it was revealed that brain responses during drinking become dulled and a sense of satisfaction is less likely to occur, resulting in increased alcohol consumption. When this mechanism was stimulated using the FGF21 inducer identified by the research group, it was shown that alcohol consumption could be reduced in both healthy mice and alcohol dependence model mice. Through analysis of how mice licked the solution, it was revealed that the reduction in alcohol consumption was not because the alcohol was made to taste bad, but because the sense of satisfaction persisted, extending the interdrink intervals and reducing the frequency of drinking.

Allulose, the FGF21 inducer with the strongest alcohol-reduction effect, is as sweet as glucose but has nearly zero calories and is already commercially available as a food additive.

This study showed that the concept of satisfaction in appetite regulation can also be applied to drinking. Furthermore, while dopamine has long been known to have the effect of promoting short-term consumption as a reward, this study demonstrated a new effect of sustaining a sense of satisfaction to suppress consumption over the long term. Moreover, the study identified abnormalities in "communication between the body and brain" that could be one of the causes of alcohol dependence. These findings may lead to the development of supplements, foods, cocktails, non-alcoholic beverages, and other products that people who want to reduce their drinking can utilize.

However, to apply these findings to society at large, it will be necessary to confirm efficacy and safety in humans, develop foods that are easy to use on a daily basis, develop more effective pharmaceuticals, and examine the legal framework to promote initiatives for pre-disease conditions that bridge the gap between food and pharmaceuticals.

Sasaki commented: "In order to elucidate the body's mechanisms that govern 'knowing when one has enough' (contentment), we are working scientifically to clarify the mechanisms by which eating and drinking generate a sense of satisfaction. We aim to use these findings to resolve health issues related to eating and drinking. For the insufficiently addressed problem of pre-disease conditions, we are researching health, pre-disease, and disease as a continuum, and aim to develop countermeasures that bridge food, medicine, and the space between them."

Matsui commented: "We are working to elucidate the fundamental mechanisms of how nutrients, hormones, and various metabolites generated in the body shape eating and drinking behaviors and sociality through metabolism and brain function. We aim to carefully understand the flow of information connecting the body and brain, and to gain a deeper understanding of the biological basis of diverse and complex behaviors."

Journal Information
Publication: Proceedings of the National Academy of Sciences
Title: Negative feedback regulation of alcohol ingestion through the FGF21-PVH oxytocin-VTA dopamine system
DOI: 10.1073/pnas.2525172122