Fructose and follistatin in acute liver disease in mice
What it found
In mice with complete hepatic insulin resistance, a high-fructose diet caused rapid fatty liver disease, and this depended on the liver protein follistatin.
In people, higher blood follistatin was linked to more liver fat and poorer adipose insulin sensitivity.
What they found
Studies in people
Human follistatin link
In 210 people, higher blood follistatin clustered with lower adipose insulin sensitivity and more liver fat. The link was strongest in people with a low BMI.
Animal and lab studies
Fructose diet and fatty liver
Mice with complete hepatic insulin resistance fed a high-fructose diet for 10 weeks developed severe fatty liver, with higher liver triglycerides, cholesterol, and free fatty acids than control mice. They also had worse glucose intolerance.
Follistatin required
Removing the liver protein follistatin or its upstream regulator FoxO1 prevented the acute fatty liver and fibrosis in these mice. Overexpressing follistatin in normal mice accelerated liver disease on the MASH diet.
Fructose and fat storage
Fructose was used to make glycerol, which helps store circulating fatty acids as fat in the liver. The authors found that fructose increased glycerol-3-phosphate in the liver, enabling re-esterification of fatty acids.
What the authors conclude
“Thus, future strategies to reduce MASLD incidence and its progression to MASH might include attenuation of hepatic FST secretion to reduce adipose lipolysis and restore healthy liver-adipose crosstalk.”
Also in their conclusions
- They conclude that dietary fructose potentiates acute MASLD during complete hepatic insulin resistance by enabling re-esterification of free fatty acids mobilized through follistatin-promoted adipose insulin resistance and lipolysis.
- They suggest that future strategies to reduce MASLD incidence and progression to MASH might include attenuation of hepatic FST secretion to reduce adipose lipolysis and restore healthy liver-adipose crosstalk.
How it was done
The authors wanted to understand how insulin resistance leads to fatty liver disease, since complete hepatic insulin resistance in mice usually causes diabetes without fatty liver.
They studied male mice with complete hepatic insulin resistance (LDKO) and control mice, feeding them a high-fructose diet or a MASH diet for up to 20 weeks. They also analyzed 210 non-diabetic people from the Tübingen Diabetes Family Study, measuring blood follistatin, adipose insulin sensitivity, and liver fat.
What it can’t tell you
- These are animal studies, so they cannot show what happens in people.
- The human part is observational, so it can show a link but not cause and effect.
- The mice had complete hepatic insulin resistance, which may not match most people with MASLD.
Who paid
- Funding
- Funded by NIDDK NIH HHS; U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases); NIA NIH HHS; U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) (from the PubMed record).
- Conflicts
- Competing interests: The authors declare the following competing interests: M.F.W. is a scientific consultant for Housey Pharmaceutical Research Laboratories; M.A.L. is a member of Colorado Research Partners (CRP). Other authors declare no competing interests, including R.T., O.S., O.T., A.A.-H., W.Q., B.H., C.W., L.G., C.B., S.H., N.S., and K.D.C.
- Authors work at
- Division of Endocrinology Boston Children's Hospital, USA; Harvard T.H. Chan School of Public Health, USA; Univ. of Colorado Anschutz School of Medicine, USA
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 26 Sep 2026. Check it against the paper before it changes what you eat. How we summarise papers · Report an error