For years, carbohydrates have taken much of the blame in debates over weight gain and metabolic health. But new research in mice suggests diets high in saturated fat may cause greater harm to the liver and metabolism than diets higher in carbohydrates, particularly when fiber and whole grains are absent.
In a study led by researchers at Penn State and published in the Journal of Nutrition, mice fed high-fat diets, including a ketogenic-style diet, experienced more weight gain, impaired glucose regulation and liver damage than mice fed a high-carbohydrate diet.
The researchers compared four diets over 16 weeks: a high-carbohydrate diet, a high-fat diet, a ketogenic diet and a standard laboratory chow rich in whole grains that served as the control. Protein intake was kept constant across the experimental diets so that only the balance of fat and carbohydrates differed.
Mice fed the ketogenic diet showed the most pronounced negative effects, including rapid weight gain, reduced ability to manage blood sugar, increased inflammation and fat accumulation in the liver. Mice on the high-fat diet also gained significant weight and developed metabolic dysfunction. By contrast, mice on the high-carbohydrate diet gained less weight and showed fewer signs of liver damage, while mice eating the whole-grain-based control diet had the most favorable health markers overall.
“Human beings and mice have very different metabolisms, but there are relevant lessons in this study for people,” said Vishal Singh, associate professor of nutritional sciences at Penn State and senior author of the study. “Some people are attracted to diets with very high fat content — like the keto diet — for weight loss. This research points to very real harm to the liver that can occur when these diets are not used appropriately.”
The fats used in the experimental diets were primarily saturated fats, while the carbohydrates were largely refined. Singh emphasized that this does not mean refined carbohydrates are inherently healthy, but rather that diet composition and quality matter more than macronutrients alone.
In a separate experiment involving mice with obesity, researchers found that adding fiber to the ketogenic diet helped stabilize weight gain and improve some metabolic markers compared with the keto diet alone. Fiber supplementation did not interfere with ketosis, a finding the researchers note may be relevant for medical uses of ketogenic diets, such as epilepsy treatment, where dietary supervision is standard.
The study was conducted in animals, not humans, and the authors caution against directly translating the results to people. The diets tested were extreme and tightly controlled, unlike real-world eating patterns. Still, the findings challenge simplified narratives that frame carbohydrates as uniquely harmful and underscore the importance of dietary context.
“A whole-grain-based diet is always a win — for mice or for people,” Singh said.
The researchers stress that there is no single dietary solution that works for everyone and that concerns about weight, liver health or metabolic function should be addressed with individualized guidance from qualified health professionals.
This research was supported in part by the European Research Council through Starting and Consolidator Grants awarded under the European Union’s Horizon 2020 research and innovation program.