Long-term ketogenic diet may cause fatty liver disease, per mouse study
Fatty molecules 'have to go somewhere,' usually the liver, scientist says
A long-term ketogenic diet, which favors fats over carbs, may promote weight loss, but it can also cause fatty liver disease and blood sugar problems, according to new research done in mice.
“One thing that’s very clear is that if you have a really high-fat diet, the lipids [fatty molecules] have to go somewhere, and they usually end up in the blood and the liver,” Amandine Chaix, PhD, the study’s senior author and an assistant professor at the University of Utah Health, said in a university news story.
The research team, who noted that such eating plans “have gained popularity as [a] therapeutic against obesity and type 2 diabetes,” launched their study to investigate the effects of a ketogenic diet on metabolic health — how the body turns nutrients such as fats and sugar into energy — over time.
“The ketogenic diet was definitely not protective in the sense of fatty liver disease,” Chaix said.
Titled “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice,” the study was published in the journal Science Advances.
In a ketogenic diet, a person minimizes their intake of carbohydrates (sugars) and instead increases the amount of fat in the diet. The goal is basically to get the body to burn fat instead of sugar as its main source of energy. This leads to the production of ketone bodies, molecules produced by the liver that work as fuel for the body.
Ketogenic diet originally developed to manage epilepsy
This type of diet was originally developed to help manage certain forms of epilepsy. Ketone bodies can help stabilize the activity of brain cells to guard against seizures, and the use of this diet in epilepsy has been studied extensively.
However, in recent years, the ketogenic diet has become increasingly popular for treating obesity and related metabolic conditions by supposedly “favoring fat usage over fat storage,” the researchers wrote. There’s some short-term research on this diet for weight loss, but very little is known about the long-term metabolic impacts of the ketogenic diet, the team noted.
“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,” said Molly Gallop, PhD, the study’s first author, who led the research as a postdoctoral fellow at the University of Utah Health. Gallop is now an assistant professor at Earlham College in Indiana.
To learn more, Chaix, Gallop, and colleagues conducted a long-term experiment in which mice were fed a ketogenic diet for nearly a year. Other mice were fed varying diets for comparison, including a high-fat eating plan designed to mimic a Western diet heavy in processed and fast foods.
The results showed that mice given the ketogenic diet had significantly less weight gain than mice on the high-fat Western diet. According to the team, that does lend credence to the idea that the ketogenic diet may help promote weight loss. But while mice on the ketogenic diet didn’t gain as much weight, they still had notable metabolic problems.
For one, mice on the ketogenic diet had very high levels of fat in their blood. Male mice also had increases in blood markers of liver damage, and analyses of liver tissue showed evidence of steatosis — an abnormal buildup of fat in liver cells, which is the hallmark of fatty liver disease.
The researchers said it’s not clear why the ketogenic diet led to steatosis in male mice but not female mice, highlighting a need for further studies into how biological sex differences influence responses to a long-term ketogenic diet.
Blood sugar regulation issues resolved after stopping diet
Additionally, the mice fed the long-term ketogenic diet had abnormally high levels of blood sugar, or glucose, similar to what was seen in mice given the high-fat Western diet. Tests showed mice on the ketogenic diet had severe glucose intolerance, essentially meaning their cells weren’t able to process glucose correctly, which resulted in abnormally high blood glucose levels.
Further tests showed that mice on the ketogenic diet had reduced ability to secrete insulin, a hormone that helps the body’s cells take in glucose. The researchers noted that this mechanism is different than what happens with the high-fat Western diet, where insulin is secreted but the body’s cells stop responding to it as well — a process known as insulin resistance.
“While impaired glucose regulation in [high-fat diet-fed] mice is likely linked to insulin resistance in the context of high insulin levels, impaired insulin secretion likely underlies glucose intolerance in [ketogenic diet-fed] mice,” the scientists wrote.
The researchers noted that the type of glucose intolerance seen in these mice can lead to notable health risks.
According to Chaix, “the problem is that when you then give these mice a little bit of carbs, their carb response is completely skewed. … Their blood glucose goes really high for really long, and that’s quite dangerous.”
I would urge anyone to talk to a health care provider if they’re thinking about going on a ketogenic diet.
Importantly, the researchers noted, the observed issues with blood sugar regulation were resolved when mice were taken off the ketogenic diet, suggesting that at least some metabolic problems may be reversed if the diet is stopped.
The team stressed that the “benefits [of a ketogenic diet] in treating epilepsy are concrete.” However, despite its help in weight loss, the researchers noted that there are potential ill effects.
“Together, these results suggest that [a] long-term [ketogenic diet] leads to multiple aberrations of metabolic parameters that caution [against its] systematic use as a health-promoting dietary intervention,” the scientists wrote.
Overall, the data suggest that following a long-term ketogenic diet could lead to metabolic problems even if it does help promote weight loss, highlighting a need for caution for people following this type of diet.
“I would urge anyone to talk to a health care provider if they’re thinking about going on a ketogenic diet,” Gallop said.
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