A new Penn State study in mice suggests that very high-fat and keto-style diets can harm liver health and drive weight gain more than high-carb diets. The findings highlight the benefits of whole grains and fiber and underscore the need for medically guided, personalized nutrition.
For years, carbohydrates have been cast as the villain of modern diets, with low-carb and keto plans promising rapid weight loss. New research from Penn State suggests the bigger danger may actually be too much fat, especially saturated fat — at least in mice.
In a 16-week study, researchers found that high-fat and ketogenic diets led to rapid weight gain, liver damage and impaired blood sugar control in mice, even though the animals ate roughly the same number of calories as other groups. Mice on a high-carbohydrate diet fared better, and those eating a whole-grain-rich chow showed the strongest markers of health.
The research, published in the Journal of Nutrition, offers a cautionary message for anyone tempted by extreme high-fat diets.
“Human beings and mice have very different metabolisms, but there are relevant lessons in this study for people,” senior author Vishal Singh, an associate professor of nutritional sciences at Penn State, said in a news release.
The team set out to test how changing the balance of fats and carbohydrates — while keeping protein constant — would affect metabolic health over time.
“We wanted to understand how altering the balance of carbohydrates and fats would affect health when the diet was maintained for 16 weeks,” added first author Umesh Goand, a postdoctoral researcher in the Penn State Department of Nutritional Sciences.
All of the experimental diets contained the same proportion of calories from protein. What differed was the ratio of carbohydrates to fats:
- A high-fat diet with substantial saturated fat
- A high-carbohydrate diet dominated by refined carbs, such as white flour and added sugars
- A ketogenic (keto) diet that was extremely high in fat and almost devoid of carbohydrates
- A standard laboratory chow rich in whole grains, which served as the control
The fats in the high-fat and keto diets were saturated fats, the kind typically solid at room temperature and commonly found in foods like butter, fatty meats and some processed snacks. Health organizations such as the American Heart Association recommend that saturated fats make up only a small fraction of daily calories because of their links to heart disease.
The carbohydrates in the experimental high-carb and keto diets were largely refined, which have been associated in past research with metabolic problems and other negative health outcomes. By contrast, the control chow was rich in whole grains and contained more fiber.
Over 16 weeks, the researchers regularly measured blood sugar and a wide range of liver health markers. They also examined liver tissue and gene activity after the diets ended.
The results were stark. Mice on the high-fat and keto diets became obese, with their body weight roughly doubling over the course of the study. Mice on the whole-grain control chow gained only about 10% — a normal increase for their age — despite similar calorie intake.
Within just two weeks, the high-fat and keto diets had impaired the animals’ ability to handle glucose, a key measure of metabolic health. Signs of liver damage and elevated blood sugar appeared early and persisted.
Mice on the keto diet showed some of the most troubling changes. They developed high levels of triglycerides, a type of blood fat linked to heart disease and stroke risk. Their livers accumulated fat deposits, and their bodies showed increased systemic inflammation and activation of genes associated with liver scarring.
“The keto diet was very damaging to the livers and overall health of mice with regular weights,” Singh added.
Keto diets work by nearly eliminating carbohydrates, pushing the body into a state called ketosis, in which it burns fat rather than glucose for fuel. That metabolic shift can have medical benefits in certain conditions, such as epilepsy, but it also places heavy demands on the liver and other organs.
Singh warned that people drawn to keto for quick weight loss may not appreciate the potential downsides.
“Most people are aware that a balanced diet is important, but 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,” he said.
“People who hear about the keto diet’s reputation for weight reduction may be tempted to try it themselves. What this research says is — don’t! This diet should only be considered when properly supervised by a physician and/or dietician,” he added.
The high-carbohydrate diet, while far from ideal, did not cause the same degree of harm. Mice eating lots of refined carbs did not continuously gain weight or develop the same level of liver damage seen in the high-fat and keto groups. Singh emphasized that a heavily processed, carb-heavy diet is not healthy, but in this experiment it was less damaging to the liver than diets overloaded with saturated fat.
The clear winner was the whole-grain-rich chow. Mice on this diet gained the least weight and had the best overall health markers.
“A whole-grain-based diet is always a win — for mice or for people,” added Singh.
Whole grains and fiber are known to support digestive health, help regulate blood sugar and cholesterol, and nourish beneficial gut microbes. Many public health guidelines recommend making whole grains and plant-based foods the foundation of daily eating patterns.
The Penn State team also ran a separate experiment in mice that already had obesity. In these animals, high-fat and keto diets again led to further weight gain. But when the keto diet was supplemented with fiber, the picture changed.
Obese mice on the fiber-enriched keto diet maintained more stable weight and showed better health indicators in several areas compared with those on the high-fat diet or the standard keto diet without extra fiber. Importantly, adding fiber did not interfere with ketogenesis, the fat-burning state that makes keto diets medically useful in some cases.
“Incorporating dietary fibers into the keto diet may reduce gastrointestinal complications associated with very high-fat diets while maintaining the therapeutic benefits of ketogenesis for patients,” Singh added.
That finding hints at a possible way to make medically necessary keto diets safer and more tolerable, though it will take human studies to know how best to translate the results.
Singh stressed that diet is highly individual and shaped by health status, genetics, lifestyle and culture.
“Over time, researchers have learned a lot about what is healthy or unhealthy based on an individual’s health status, but there is no single dietary magic bullet for weight loss or any other metabolic health concern,” he said.
Rather than chasing the latest trend, Singh encouraged people to seek evidence-based guidance tailored to their own needs.
“Anyone who experiences health problems or is concerned about their diet should talk to their physician or a registered dietician to develop a plan, based on research, that fits their specific needs and life circumstances,” he said.
While the study was conducted in mice, not humans, it reinforces a message that nutrition scientists have been building for years: diets centered on whole grains, fruits, vegetables and other fiber-rich foods tend to support better long-term health than patterns dominated by saturated fats or highly processed ingredients. As research continues, the goal is not to find a one-size-fits-all solution, but to help people make informed, sustainable choices that protect both their weight and their organs — especially the hard-working liver.
Source: Pennsylvania State University