Summary: In the short term, a ketogenic diet can improve metabolic health and support weight loss. However, negative effects begin to appear after about a week in mice. When mice consumed a very high-fat, very low-carbohydrate diet for longer than seven days, they ate more fat than they could metabolize and showed increased risk factors for diabetes and obesity.
Source: Yale
A ketogenic diet — supplying almost all calories from fat and very few from carbohydrates — produces clear metabolic benefits in the short term but can cause harmful changes after roughly one week in mice, according to researchers at Yale.
The Yale study identifies immune cells called gamma delta (γδ) T cells as a key link between the diet’s early advantages and its later drawbacks. These tissue-protective immune cells expand when the body shifts to burning fats, and their activity appears to reduce inflammation and improve glucose control initially. But continued, unrestricted consumption of a ketogenic-style diet eventually depletes these protective cells in fat tissue, coinciding with worsening metabolic health.
Lead investigator Vishwa Deep Dixit of the Yale School of Medicine explains that the ketogenic diet lowers circulating glucose by restricting carbohydrates, which prompts the body to use stored fats for energy. This shift produces ketone bodies—alternative fuel molecules such as β-hydroxybutyrate—that the body uses instead of glucose. The rise in ketone bodies triggers expansion of γδ T cells throughout adipose (fat) tissue, helping limit inflammation and protecting metabolic function.
In the Yale laboratory experiments, mice on the ketogenic diet showed lower blood sugar and reduced inflammation after about a week, consistent with improved metabolic readouts. These short-term benefits mirror anecdotal reports from people who follow keto for weight loss and metabolic improvement, a trend fueled in part by public figures who have promoted the diet.
However, the researchers observed that the metabolic state induced by the diet is paradoxical: the body is prompted to both burn fat and store fat. When mice continued eating the high-fat, low-carbohydrate diet beyond one week without restriction, they consumed more fat than they could safely oxidize. Over time, this imbalance led to obesity and impaired glucose control, and adipose-resident γδ T cells became depleted.
“They lose the protective γδ T cells in the fat,” Dixit said, a change that corresponds with the diet’s transition from beneficial to harmful in these animal models.
These findings are important because they clarify mechanisms linking metabolism and immune function. Emily Goldberg, a postdoctoral fellow involved in the research, noted that the study highlights how dietary fuel use coordinates with immune cells to maintain healthy tissue function. By expanding γδ T cells, short-term ketogenesis appears to restrain inflammation and support metabolic health; by contrast, sustained, unrestricted ketogenic feeding can undermine those same protective immune responses.
The research team cautions that mouse results do not directly translate into clinical recommendations for humans. Larger, controlled clinical trials are needed to determine whether short-term ketogenic diets can be used safely and effectively in people—especially those who are overweight or prediabetic—and to define optimal duration and dosing. Dixit emphasized that before prescribing such an approach, researchers must understand both the metabolic benefits and any potential harms.
There is a public health rationale for further study. According to the Centers for Disease Control and Prevention, about one in three American adults—roughly 84 million people—have prediabetes, a condition marked by elevated blood sugar that increases the risk of progressing to type 2 diabetes, heart disease, and stroke. Most people with prediabetes are unaware of their condition.
The Yale study therefore provides an early, mechanistic explanation for why ketogenic diets might offer metabolic advantages in the short term while posing risks when followed long term without control. It offers a foundation for future human trials that could test whether time-limited, carefully monitored ketogenic interventions might yield therapeutic benefit without the longer-term harms observed in mice.
Funding: The research received partial support from grants provided by the National Institutes of Health.
Source:
Yale
Media Contacts:
Brita Belli – Yale
Image Source:
The image is adapted from the Yale news release.
Original Research: Closed access
“Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue”. Emily L. Goldberg, Irina Shchukina, Jennifer L. Asher, Sviatoslav Sidorov, Maxim N. Artyomov, Vishwa Deep Dixit. Nature Metabolism. doi: 10.1038/s42255-019-0160-6.
Abstract
Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue
Ketone bodies function as essential alternative fuels when glucose is scarce during starvation or prolonged exercise. A commonly used ketogenic diet (KD), extremely high in fat and very low in carbohydrates, drives reliance on β-hydroxybutyrate for ATP production and reduces NLRP3-mediated inflammation. Because KD is so high in fat, questions remain about how ketogenesis affects adipose tissue, inflammation, and energy balance. Using single-cell RNA sequencing of adipose-resident immune cells, the study shows that KD expands metabolically protective γδ T cells that help restrain inflammation. Notably, long-term, ad libitum KD feeding in mice induces obesity, harms metabolic health, and depletes adipose-resident γδ T cells. Mice lacking γδ T cells have impaired glucose regulation. These results indicate γδ T cells mediate protective immunometabolic responses that connect fatty-acid–driven fuel use to reduced adipose inflammation.