The hidden link between sugar cravings and heavy drinking

Scientists have known for years that alcohol and sugar can damage the liver and influence your choices in ways that feel automatic. A new animal study now suggests they may do so through the same unseen route in the body, one that controls how fructose is made and used. When that pathway was blocked in mice and rats, the animals drank far less alcohol and were protected from the liver disease that often follows long term drinking.

The findings hint at a shared biological drive behind a sweet tooth and heavy alcohol use, something that might help explain why cravings can feel so hard to shake.

Alcohol and sugar activate many of the same reward circuits. People with alcohol use disorder often prefer sweet foods, and their children show a similar taste. Lab animals behave the same way. Rats that consume more ethanol will also take in more sugar, and animals that get sugar usually drink more alcohol. Many of these effects trace back to fructose, a simple sugar found in sweetened drinks and processed foods.

In mice, fructose boosts dopamine and raises levels of a protein called ΔFosB in the nucleus accumbens, a region linked to reinforcement and addiction. Alcohol raises ΔFosB as well. In earlier tests, mice kept choosing fructose even when they could not taste sweetness, which suggested that the craving came from processes inside the body rather than flavor alone. Sugar and alcohol also harm the liver in similar ways. Both can lead to fat buildup, inflammation and scarring. When animals receive ethanol and fructose together, the liver injury becomes even more severe.

Your body can make fructose from glucose through a chain of chemical steps known as the polyol pathway. An enzyme called aldose reductase converts glucose into sorbitol, which then becomes fructose. Another enzyme named ketohexokinase, mainly its KHK C form, breaks down that fructose inside cells. This pathway has been tied to metabolic dysfunction and kidney injury. The new research shows that alcohol can switch it on.

Alcohol is a hyperosmolar substance. When it was given to mice in a concentrated form, the number of particles in their portal blood rose sharply. This rise triggered aldose reductase in the liver. Within days, sorbitol and fructose climbed as well. When the same amount of alcohol was diluted, these changes almost disappeared. That pattern revealed that the osmotic effect of alcohol, rather than alcohol itself, was driving the internal production of fructose.

Mice missing aldose reductase drank less alcohol and preferred it less in classic two bottle tests. Animals with only half the normal amount of the enzyme sat between the two groups. The stronger the block in this pathway, the weaker the draw toward alcohol. These results pointed to newly made fructose as an important part of alcohol seeking.

To look more directly at fructose breakdown, scientists studied mice lacking both KHK A and C. These animals drank much less in long studies where alcohol concentrations rose step by step. Male and female knockout mice showed lower preference and daily intake at all tested alcohol levels. Animals missing only KHK A drank like their normal peers. That confirmed that KHK C plays the major role.

When researchers measured alcohol reward through place preference tests, normal mice spent more time in a chamber paired with ethanol. Mice without KHK barely shifted their preference. Their brain chemistry reflected this.

After long term drinking, normal animals showed higher ΔFosB and increases in two of its targets, Glur2 and Cdk5. Knockout mice showed none of those changes. They either drank too little alcohol to trigger those shifts or were less responsive to alcohol’s signals in those circuits.

Because fructose metabolism is especially active in the liver and intestine, scientists deleted KHK in each organ. Mice lacking KHK only in liver cells still drank less than their littermates. When alcohol intake was balanced between groups for more than a year, the difference in liver health was stark.

Normal animals developed heavy fat buildup, inflammation and fibrosis. Liver specific knockouts were largely protected even though they consumed similar amounts of alcohol.

In the intestine, alcohol raised aldose reductase, KHK, sorbitol and fructose. Mice missing intestinal KHK drank less and had lower preference. These gut studies also uncovered a hormone link. Alcohol normally lowers glucagon like peptide 1, a hormone known to reduce voluntary drinking. When fructose metabolism was blocked, GLP 1 levels stayed higher, which may help explain why the animals consumed less.

To test whether the pathway could be targeted after drinking habits had already formed, the team used mice that lost KHK only after receiving tamoxifen. Before treatment, their drinking looked normal. Once KHK was deleted, their alcohol intake dropped and their ability to clear alcohol weakened, hinting at reduced metabolic tolerance.

A small molecule inhibitor named CRP427 produced similar effects. This drug slows fructose metabolism and collects in the liver. When high drinking mouse and rat strains received CRP427, their alcohol intake and preference fell within days. That shift raises the possibility of a therapy that blocks fructose metabolism as a way to lower drinking and protect the liver.

This work suggests that alcohol and sugar may drive disease through the same metabolic switch. By targeting fructose production or breakdown, future treatments could help people reduce drinking and shield the liver from harm.

This approach may also help those at risk for diet related liver disease since the same pathway drives metabolic dysfunction.

If these results translate to people, blocking fructose metabolism could open the door to new therapies for alcohol use disorder and alcohol associated liver disease.

Research findings are available online in the journal Nature Metabolism.

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