A new study from University of Utah Health reveals that while the ketogenic diet prevents weight gain in mice, it leads to serious metabolic problems like fatty liver disease and impaired blood sugar control over time. Male mice experienced the most severe effects, including liver damage. The findings, published in Science Advances, question the diet's long-term safety for metabolic health.
Researchers at University of Utah Health conducted a long-term experiment on adult male and female mice to assess the ketogenic diet's effects on metabolism. The mice followed one of four diets for nine months or more: a high-fat Western diet, a low-fat high-carbohydrate diet, a traditional ketogenic diet with nearly all calories from fat, or a protein-matched low-fat diet. Throughout the study, the team monitored body weight, food intake, blood lipids, liver fat accumulation, and blood sugar and insulin levels. They also analyzed gene activity in pancreatic cells and used microscopy to examine cellular changes.
Mice on the ketogenic diet gained significantly less weight than those on the Western diet, an effect observed in both sexes. However, any weight increase was primarily fat mass rather than lean tissue. Despite this benefit, the diet caused notable metabolic disruptions. Within days, excess fats accumulated in the blood and liver, leading to fatty liver disease—a marker of metabolic illness often tied to obesity.
"One thing that's very clear is that if you have a really high-fat diet, the lipids have to go somewhere, and they usually end up in the blood and the liver," said Amandine Chaix, PhD, assistant professor of nutrition and integrative physiology at University of Utah Health and senior author of the study. Male mice developed severe fatty liver disease and impaired liver function, while females showed no significant liver fat buildup. The researchers plan further investigation into this sex-based difference.
Blood sugar regulation also suffered. After two to three months, keto-fed mice had low blood sugar and insulin levels, but reintroducing carbohydrates caused dangerously prolonged high blood glucose spikes due to inadequate insulin release from stressed pancreatic cells. Chaix noted, "The problem is that when you then give these mice a little bit of carbs, their carb response is completely skewed... and that's quite dangerous."
Encouragingly, blood sugar control improved after removing the mice from the diet, indicating some reversibility. The study, titled "A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice," appears in Science Advances (2025; 11(38)). Lead author Molly Gallop, PhD, emphasized the gap in prior research: "We've seen short-term studies and those just looking at weight, but not really any studies looking at what happens over the longer term or with other facets of metabolic health."
Though conducted in mice, the results highlight potential risks for humans using the diet for weight loss or managing obesity and type 2 diabetes. Gallop advised, "I would urge anyone to talk to a health care provider if they're thinking about going on a ketogenic diet."
