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Study · Nature communications · 2025Conflicts declared

Fructose, liver insulin resistance and fatty liver in mice and people

Tao R, Stöhr O, Tok O, et al · Free full text

What it found

In mice with complete liver insulin resistance, fructose diets rapidly caused fatty liver disease by helping the liver store fat released from body fat.

In 210 people at risk of diabetes, higher levels of a related protein in the blood matched lower fat-tissue insulin sensitivity and more liver fat.

What they found

Studies in people

Follistatin linked to liver fat

Among 210 people at risk of metabolic disease, those with the highest blood levels of follistatin had the most liver fat. These individuals also had the poorest insulin response in their fat tissue and the least fat stored in their hips and thighs.

Animal and lab studies

Fructose caused fatty liver

Mice whose livers completely ignored insulin developed severe fatty liver within 10 weeks when fed a diet rich in fructose, fat and cholesterol. A simpler diet of 60% fructose also caused fatty liver in these mice, but without scarring.

Fat came from body stores

Using labeled fructose, the researchers showed the sugar did not build new fat chains in the mouse liver. Instead, it helped the liver attach circulating fats, released from body fat stores, into stored liver fat.

Follistatin drove fat release

A protein called follistatin, made by the insulin-resistant mouse liver, forced body fat to release stored fat into the blood. Removing this protein in mice prevented fatty liver, while adding extra follistatin to normal mice worsened it.

What the authors conclude

  • They conclude that dietary fructose can drive fatty liver disease even when the liver is completely resistant to insulin, by providing a chemical backbone that helps store fats released from body fat.
  • The authors suggest that lowering follistatin production in the liver might be a future way to reduce fatty liver disease and its progression to liver scarring.

How it was done

Scientists thought that insulin working inside the liver was needed for fatty liver disease to develop. They wanted to test whether fructose could cause fatty liver even when the liver completely ignores insulin.

They fed genetically modified mice with total liver insulin resistance several diets, including one containing 60% fructose and another high-fat diet with added fructose and cholesterol, for 10 to 20 weeks. They also measured blood proteins, insulin sensitivity and liver fat in 210 non-diabetic people who had a family history of type 2 diabetes.

What it can’t tell you

  • These findings come mostly from mice engineered to have total liver insulin resistance, which may not match how human livers respond to fructose.
  • The special mouse diets used very high amounts of fructose, fat and cholesterol that do not directly represent a typical human diet.
  • The measurements in 210 people were taken at one point in time, so they can show a link between follistatin and liver fat but cannot prove one causes the other.

The paper

Title
Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance
Type
Study
Evidence
Studies in people · animals · lab
Summarised from
Full text
Cite
Tao R, Stöhr O, Tok O, et al (2025). Fructose and follistatin potentiate acute MASLD during complete hepatic insulin resistance. Nature communications. doi:10.1038/s41467-025-66296-5Free full textPubMed 41276502DOI

Summary written 30 Sep 2026. Check it against the paper before it changes what you eat. How we summarise papers · Report an error