A long-term study published in Science Advances has found that while a ketogenic diet limited weight gain in mice, prolonged adherence triggered metabolic disruptions, including impaired insulin secretion, fatty liver disease and elevated blood lipids, raising questions about the diet’s long-term safety as it continues to gain popularity for weight loss and metabolic health.
The research, conducted by scientists at University of Utah Health, examined adult male and female mice placed on one of four diets for nearly a year: a classic ketogenic diet providing about 90% of calories from fat, a high-fat Western-style diet, a low-fat high-carbohydrate diet, and a protein-matched low-fat control. The study monitored body weight, fat composition, blood glucose, insulin dynamics, lipid profiles and liver function, alongside cellular and genetic mechanisms linked to metabolic regulation.
While mice on the ketogenic diet gained significantly less weight than those fed a Western-style high-fat diet, they remained heavier than mice on a low-fat diet. In male mice, nearly all weight gain on the ketogenic diet came from fat mass, with no measurable increase in lean mass. Female mice showed increases in both fat and lean mass, though their overall fat accumulation remained lower than that observed in females on the Western diet. When mice were switched from a high-fat diet to a ketogenic diet, weight loss occurred, but a low-fat diet produced nearly double the reduction in body weight.
“Most of what we know about ketogenic diets comes from short-term studies or research focused narrowly on body weight,” said Molly Gallop, PhD, Assistant professor of anatomy and physiology, Earlham College and lead author of the study, who conducted the research as a postdoctoral fellow, University of Utah Health. “We wanted to understand what happens to broader metabolic health when this diet is followed long term.”
Despite weight control benefits, the ketogenic diet produced marked metabolic abnormalities. Over time, mice developed severe glucose intolerance that worsened with prolonged exposure. Unlike mice on the Western diet, which became insulin resistant, ketogenic-fed mice remained insulin sensitive but were unable to regulate blood glucose because their pancreas failed to secrete adequate insulin when carbohydrates were introduced.
“The paradox is that these animals appear metabolically flexible in some respects but fail at a very basic level when challenged with glucose,” said Amandine Chaix, PhD, assistant professor of nutrition and integrative physiology, University of Utah Health and senior author of the study. “Blood sugar rises sharply and remains elevated, which is a dangerous pattern.”
To understand why insulin secretion failed, researchers used transcriptomic profiling and advanced electron microscopy. They found that pancreatic beta cells in ketogenic-fed mice contained sufficient insulin and were structurally intact but exhibited stress within the endoplasmic reticulum and Golgi apparatus, systems responsible for processing and transporting proteins. Microscopy revealed dilated and fragmented Golgi networks, effectively creating a cellular bottleneck that prevented insulin granules from being released into the bloodstream.
The study also identified pronounced hyperlipidemia. Ketogenic-fed mice showed significantly higher levels of triglycerides and free fatty acids than all other diet groups, including those on the high-fat Western diet. In male mice, this lipid overload contributed to hepatic steatosis, or fatty liver disease, along with elevated liver enzymes indicating impaired liver function. Female mice did not develop significant liver fat accumulation, a sex-specific difference researchers say warrants further investigation.
“One thing that becomes clear with extreme high-fat diets is that lipids have limited places to go,” Chaix said. “They tend to accumulate in the blood and the liver.”
Notably, many of the metabolic disruptions were reversible. When male mice were transitioned from a long-term ketogenic diet back to a low-fat diet, glucose tolerance normalized within weeks. Additional experiments showed that a high-fat, high-protein diet caused similar insulin secretion defects, suggesting that the combination of very high fat and very low carbohydrate intake, rather than ketosis itself, was responsible for the observed effects.
Although conducted in mice, the findings raise concerns growing around obesity and metabolic disease in Mexico, where more than 70% of adults live with overweight or obesity and related conditions continue to strain public health systems. Obesity has been formally recognized as a public health emergency, with associated diseases such as Type 2 diabetes, cardiovascular conditions and hypertension accounting for a substantial share of premature deaths and health care spending.
As a response, Mexico has introduced taxes on sugary beverages, mandated front-of-package warning labels and restricted the sale of high-calorie packaged foods in schools, replacing them with nutritionally regulated options. These measures remain relatively recent, and their long-term impact has yet to be fully measured, but they reflect a shift toward prevention and lifestyle-focused health strategies.
At the same time, changes in consumer behavior have complicated nutrition outcomes. During the COVID-19 pandemic, demand for food and beverage delivery services rose sharply, reinforcing reliance on convenience-based diets that are often calorie-dense and nutritionally imbalanced. Analysts note that home cooking has declined as time constraints and digital platforms reshape eating habits.
This environment has created space for new nutrition-focused technologies and services. Consumer-facing applications such as MyRealFood and Yuka allow users to scan food products, evaluate nutritional quality and receive guidance aimed at reducing ultra-processed food consumption. More clinically oriented platforms are also emerging, offering personalized interventions rather than standardized diet plans.
One such company is nutriADN, which applies genetic testing to inform nutrition, exercise and lifestyle recommendations. According to Gustavo Rodríguez, CEO, nutriADN, the goal is not to promote restrictive dietary trends but to align nutritional decisions with individual metabolic predispositions.
“There is a widespread perception that healthy living requires expensive products or extreme diets,” said Rodríguez. “But the fundamentals remain balanced nutrition, regular physical activity, adequate sleep and stress management.”
Rodríguez noted that genetic and metabolic data can help health professionals tailor interventions, particularly for individuals with predispositions to chronic conditions such as diabetes, cardiovascular disease or obesity. He emphasized that personalized guidance may help patients avoid cycles of restrictive dieting followed by metabolic rebound.
Clinical experts in Mexico have also cautioned against the uncritical adoption of diets such as keto without adequate medical supervision. Hospital-based obesity management continues to rely primarily on hypocaloric diets, behavioral interventions and physical activity, with pharmacological treatments and bariatric surgery reserved for specific cases. Several specialists have warned that limited training in nutrition can lead to inconsistent or inappropriate dietary prescriptions.
Against this backdrop, the Utah study adds evidence to a growing debate over the long-term metabolic consequences of extreme dietary patterns. While ketogenic diets may offer short-term benefits for weight reduction or seizure control, the findings suggest that sustained use could carry tradeoffs that are not immediately apparent when weight is the primary outcome measured.
The researchers stressed that their findings should not be interpreted as direct clinical guidance for humans but rather as a signal that long-term metabolic effects deserve closer scrutiny. Gallop advised individuals considering ketogenic diets to consult health care providers and to view diet as part of a broader, sustainable approach to metabolic health.