How ketogenic diets curb inflammation

September 25, 2017 by Devika G Bansal, University of California, San Francisco
How ketogenic diets curb inflammation
Credit: University of California, San Francisco

Ketogenic diets – extreme low-carbohydrate, high-fat regimens that have long been known to benefit epilepsy and other neurological illnesses – may work by lowering inflammation in the brain, according to new research by UC San Francisco scientists.

The UCSF team has discovered a molecular key to the diet's apparent effects, opening the door for new therapies that could reduce harmful brain inflammation following stroke and brain trauma by mimicking the beneficial effects of an extreme low-carb diet.

"It's a key issue in the field – how to suppress inflammation in the brain after injury," said Raymond Swanson, MD, a professor of neurology at UCSF, chief of the neurology service at the San Francisco Veterans Affairs Medical Center, and senior author of the new study.

In the paper, published online Sept. 22 in the journal Nature Communications, Swanson and his colleagues found the previously undiscovered mechanism by which a low-carbohydrate diet reduces inflammation in the brain. Importantly, the team identified a pivotal protein that links the diet to inflammatory genes, which, if blocked, could mirror the anti-inflammatory effects of ketogenic diets.

"The ketogenic is very difficult to follow in everyday life, and particularly when the patient is very sick," Swanson said. "The idea that we can achieve some of the benefits of a by this approach is the really exciting thing here."

Low-Carb Benefits

The high-fat, low-carbohydrate regimen of ketogenic diets changes the way the body uses energy. In response to the shortage of carb-derived sugars such as glucose, the body begins breaking down fat into ketones and ketoacids, which it can use as alternative fuels.

In rodents, ketogenic diets – and caloric restriction, in general – are known to reduce inflammation, improve outcomes after brain injury, and even extend lifespan. These benefits are less well-established in humans, however, in part because of the difficulty in maintaining a ketogenic state.

In addition, despite evidence that ketogenic diets can modulate the in rodents, it has been difficult to tease out the precise molecular nuts and bolts by which these diets influence the immune system.

Intricate Molecular Waltz

In the new study, the researchers used a small molecule called 2-deoxyglucose, or 2DG, to block glucose metabolism and produce a ketogenic state in rats and controlled laboratory cell lines. The team found that 2DG could bring inflammation levels down to almost control levels.

"I was most surprised by the magnitude of this effect, because I thought ketogenic diets might help just a little bit," Swanson said. "But when we got these big effects with 2DG, I thought wow, there's really something here."

The team further found that reduced lowered a key barometer of energy metabolism – the NADH/NAD+ ratio – which in turn activated a protein called CtBP that acts to suppress activity of inflammatory genes.

In a clever experiment, the researchers designed a drug-like peptide molecule that blocks the ability of CtBP to enter its inactive state – essentially forcing the protein to constantly block inflammatory gene activity and mimicking the effect of a ketogenic state.

Peptides, which are small proteins, don't work well themselves as drugs because they are unstable, expensive, and people make antibodies against them. But other molecules that act the same way as the peptide could provide ketogenic benefits without requiring extreme dietary changes, Swanson said.

The study has applications beyond brain-related inflammation. The presence of excess glucose in people with diabetes, for example, is associated with a pro-inflammatory state that often leads to atherosclerosis, the buildup of fatty plaques that can block key arteries. The new study could provide a way of interfering with the relationship between the extra glucose in patients with diabetes and this inflammatory response.

Explore further: Eat fat, live longer? Mouse study shows a high fat diet increases longevity, strength

More information: Yiguo Shen et al. Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP, Nature Communications (2017). DOI: 10.1038/s41467-017-00707-0

Related Stories

Eat fat, live longer? Mouse study shows a high fat diet increases longevity, strength

September 5, 2017
As more people live into their 80s and 90s, researchers have delved into the issues of health and quality of life during aging. A recent mouse study at the UC Davis School of Veterinary Medicine sheds light on those questions ...

Ketogenic diet improves healthspan and memory in aging mice

September 5, 2017
A ketogenic diet significantly improved memory in aging mice and increased the animal's chances of surviving to old age. Results of the study from Eric Verdin's lab at the Buck Institute for Research on Aging in Novato, CA ...

Do ketogenic diets help you lose weight?

September 20, 2017
Is a ketogenic diet effective for weight loss? The answer depends on whether it achieves a reduction in total kilojoule intake or not.

What are ketogenic diets? Can they treat epilepsy and brain cancer?

September 5, 2017
Ketogenic diets are back in the news with claims they are a "cure-all". Research shows that in epilepsy not controlled by current treatment, around 50% of children and adults following ketogenic diets have a reduction in ...

Low-carb, high-fat diets may reduce seizures in tough-to-treat epilepsy

October 29, 2014
Diets high in fat and low in carbohydrates, such as the ketogenic or modified Atkins diet, may reduce seizures in adults with tough-to-treat epilepsy, according to a review of the research published in the October 29, 2014, ...

Review: Ketogenic diets suppress appetite despite weight loss

November 21, 2014
(HealthDay)—A review of evidence supports that ketogenic diets suppress appetite despite weight loss. The research was published online Nov. 17 in Obesity Reviews.

Recommended for you

Researchers report protein kinase as the switch controlling obesity and diabetes

July 18, 2018
One of the research lines targeting the worldwide obesity epidemic is the manipulation of brown adipose tissue, a 'good' type of fat that burns lipids to maintain an appropriate body temperature. Researchers at the Centro ...

New retinal ganglion cell subtypes emerge from single-cell RNA sequencing

July 18, 2018
Single-cell sequencing technologies are filling in fine details in the catalog of life. Researchers at the University of Connecticut Health Center (UConn Health) and The Jackson Laboratory (JAX) have identified 40 subtypes ...

Researchers develop novel bioengineering technique for personalized bone grafts

July 18, 2018
Scientists from the New York Stem Cell Foundation (NYSCF) Research Institute have developed a new bone engineering technique called Segmental Additive Tissue Engineering (SATE). The technique, described in a paper published ...

Scientists find malformations and lower survival rates in zebrafish embryos exposed to cannabinoids

July 16, 2018
Exposure to the main chemical components of cannabis has a detrimental effects on developing zebrafish embryos, according to a new study conducted by University of Alberta biologists.

Fetal gene therapy prevents fatal neurodegenerative disease

July 16, 2018
A fatal neurodegenerative condition known as Gaucher disease can be prevented in mice following fetal gene therapy, finds a new study led by UCL, the KK Women's and Children's Hospital and National University Health System ...

New study finds that fat consumption is the only cause of weight gain

July 13, 2018
Scientists from the University of Aberdeen and the Chinese Academy of Sciences have undertaken the largest study of its kind looking at what components of diet—fat, carbohydrates or protein—caused mice to gain weight.

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

FainAvis
not rated yet Sep 27, 2017
I am male, 75 yo, diabetic type 2.
Twice I have taken a large dose of coconut oil, a desert spoon full, then naturally started to run. At 3 km (1.86 miles) I was still running, not puffing or even heavy breathing, heart not pounding at all, and head clear. Then over about 50 meters (160 ft) my muscles went to jelly, and my brain faded to just short of unconsciousness. It was all I could do to grasp something to break my fall.
In both cases I recovered in a few minutes.
I surmise that when I set off running I was in deep ketosis, and burning ketones from coconut fat almost exclusively. When I collapsed I had run out of ketone fuel.
I do not think inflammation had anything to do with my quickly changing metabolic status, it was only suddenly running on empty.
'Tis a cautionary tale that I tell.

befreer
not rated yet Oct 12, 2017
sir-

a typical male has approximately 80,000 kcal of available energy in their adipose tissue (fat cells).

your fat cells would easily allow you to continue using ketones as fuel...if you WERE PROPERLY FAT ADAPTED prior to running!

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.