Summary: In the short term, a ketogenic diet can help improve health as well as assist in weight loss. However, the negative effects of the keto diet start to appear after one week. Mice who were fed a ketogenic-style diet for more than seven days consumed more fat than they could burn, and had an increased risk of developing diabetes and obesity.
A ketogenic diet — which provides 99% of calories from fat and only 1% from carbohydrates — produces health benefits in the short term, but negative effects after about a week, Yale researchers found in a study of mice.
The results offer early indications that the keto diet could, over limited time periods, improve human health by lowering diabetes risk and inflammation. They also represent an important first step toward possible clinical trials in humans.
The keto diet has become increasingly popular as celebrities, including Gwyneth Paltrow, Lebron James, and Kim Kardashian, have touted it as a weight-loss regimen.
In the Yale study, published in the Jan. 20 issue of Nature Metabolism, researchers found that the positive and negative effects of the diet both relate to immune cells called gamma delta T-cells, tissue-protective cells that lower diabetes risk and inflammation.
A keto diet tricks the body into burning fat, said lead author Vishwa Deep Dixit of the Yale School of Medicine. When the body’s glucose level is reduced due to the diet’s low carbohydrate content, the body acts as if it is in a starvation state — although it is not — and begins burning fats instead of carbohydrates. This process in turn yields chemicals called ketone bodies as an alternative source of fuel. When the body burns ketone bodies, tissue-protective gamma delta T-cells expand throughout the body.
This reduces diabetes risk and inflammation, and improves the body’s metabolism, said Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology. After a week on the keto diet, he said, mice show a reduction in blood sugar levels and inflammation.
But when the body is in this “starving-not-starving” mode, fat storage is also happening simultaneously with fat breakdown, the researchers found. When mice continue to eat the high-fat, low-carb diet beyond one week, Dixit said, they consume more fat than they can burn, and develop diabetes and obesity.
“They lose the protective gamma delta T-cells in the fat,” he said.
Long-term clinical studies in humans are still necessary to validate the anecdotal claims of keto’s health benefits.
“Before such a diet can be prescribed, a large clinical trial in controlled conditions is necessary to understand the mechanism behind metabolic and immunological benefits or any potential harm to individuals who are overweight and pre-diabetic,” Dixit said.
There are good reasons to pursue further study: According to the Centers for Disease Control, approximately 84 million American adults — or more than one out of three — have prediabetes (increased blood sugar levels), putting them at higher risk of developing type 2 diabetes, heart disease, and stroke. More than 90% of people with this condition don’t know they have it.
“Obesity and type 2 diabetes are lifestyle diseases,” Dixit said. “Diet allows people a way to be in control.”
With the latest findings, researchers now better understand the mechanisms at work in bodies sustained on the keto diet, and why the diet may bring health benefits over limited time periods.
“Our findings highlight the interplay between metabolism and the immune system, and how it coordinates maintenance of healthy tissue function,” said Emily Goldberg, the postdoctoral fellow in comparative medicine who discovered that the keto diet expands gamma-delta T cells in mice.
If the ideal length of the diet for health benefits in humans is a subject for later studies, Dixit said, discovering that keto is better in small doses is good news, he said: “Who wants to be on a diet forever?”
Funding: The research was funded in part by grants from the National Institutes of Health.
Brita Belli – Yale
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.
Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue
Ketone bodies are essential alternative fuels that allow humans to survive periods of glucose scarcity induced by starvation and prolonged exercise. A widely used ketogenic diet (KD), which is extremely high in fat with very low carbohydrates, drives the host into using β-hydroxybutyrate for the production of ATP and lowers NLRP3-mediated inflammation. However, the extremely high fat composition of KD raises the question of how ketogenesis affects adipose tissue to control inflammation and energy homeostasis. Here, by using single-cell RNA sequencing of adipose-tissue-resident immune cells, we show that KD expands metabolically protective γδ T cells that restrain inflammation. Notably, long-term ad libitum KD feeding in mice causes obesity, impairs metabolic health and depletes the adipose-resident γδ T cells. In addition, mice lacking γδ T cells have impaired glucose homeostasis. Our results suggest that γδ T cells are mediators of protective immunometabolic responses that link fatty acid–driven fuel use to reduced adipose tissue inflammation.