Long-term effects of keto: High-fat diet potentially harms metabolism

New research sheds light on the long-term effects of the ketogenic diet, raising important questions about its safety and efficacy for improving metabolic health.

Historically, the ketogenic diet treated epilepsy. It has recently gained popularity for weight loss and management of conditions like obesity and type 2 diabetes.

The new mouse-model study suggests that the diet can potentially have dangerous impacts on metabolic health, including how the body processes fats and carbohydrates.

“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,” says lead study author Molly Gallop, Ph.D., assistant professor of anatomy and physiology at Earlham College. Gallop led the study as a postdoctoral fellow in nutrition and integrative physiology at the University of Utah (U of U) Health, US.

Four diets investigated

The researchers conducted a long-term study on mice, which placed male and female adults on one of four diets: a high-fat Western diet, a low-fat high-carbohydrate diet, a classic ketogenic diet where almost all calories come from fat, and a protein-matched low-fat diet.

The mice were free to eat as much as they wanted for nine months or longer.

Throughout the study, the team measured the mice’s body weight, food intake, blood fat profiles, liver fat accumulation, and blood sugar and insulin levels.

They also examined which genes were active in the pancreatic cells that produce insulin.

Finally, they used advanced microscopy to uncover the cellular mechanisms behind the observed metabolic changes.

The ketogenic diet successfully prevented weight gain in both sexes compared to the high-fat Western diet. Mice on the ketogenic diet also maintained significantly lower body weights, but weight gain in this group was mainly increased fat mass rather than lean mass.

Keto is linked to fatty liver disease

Despite this clear benefit, mice fed the ketogenic diet developed “severe metabolic complications,” with some changes starting within days.

“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,” says senior author Amandine Chaix, Ph.D., assistant professor of nutrition and integrative physiology at U of U Health.

Fat accumulating in the liver, known as fatty liver disease, is a hallmark of metabolic disease associated with obesity. “The ketogenic diet was definitely not protective in the sense of fatty liver disease,” Chaix adds.

The researchers noticed significant differences in how male and female mice responded to the ketogenic diet. Males developed severe fatty liver and had worse liver function, a key indicator of metabolic disease, while females had no significant buildup of fat in the liver.

In future research, the scientists plan to explore why female mice didn’t get fatty liver disease.

Keto may harm blood sugar regulation

The study also revealed a paradox in blood sugar regulation. After two to three months on the ketogenic diet, mice had low blood sugar and insulin levels.

“The problem is that when you then give these mice a little bit of carbs, their carb response is completely skewed,” Chaix says. “Their blood glucose goes really high for really long, and that’s quite dangerous.”

Mice couldn’t regulate their blood sugar properly because cells in the pancreas weren’t secreting enough insulin, the researchers discovered. Probably due to chronically high levels of fat in their environment, pancreatic cells showed signs of stress, unable to move proteins around like they should. 

The researchers believe that the impaired blood sugar regulation is caused by this cellular stress, but identifying the exact mechanism is a future research direction.

Importantly, problems with blood sugar regulation reversed when mice went off the ketogenic diet, suggesting that at least some metabolic issues may not be permanent if the diet is stopped.

While mice and humans differ, the findings reveal previously unexplored long-term negative metabolic health risks that individuals considering the ketogenic diet should take into account. “I would urge anyone to talk to a health care provider if they’re thinking about going on a ketogenic diet,” Gallop cautions.

The results are published in Science Advances, titled “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice.”

In human studies, keto diets have previously contributed to “dramatic improvements” in metabolism. However, one study published this month found that these high-fat diets may fuel obesity-related fatty acids that accelerate cancer tumor growth.