Yale University. US: Researchers at Yale School of Medicine have found that a compound
produced by the body when dieting or fasting can block a part of the
immune system involved in several inflammatory disorders such as type 2
diabetes, atherosclerosis, and Alzheimer’s disease.
In their
study, published in the Feb. 16 online issue of Nature Medicine, the
researchers described how the compound β-hydroxybutyrate (BHB) directly
inhibits NLRP3, which is part of a complex set of proteins called the
inflammasome. The inflammasome drives the inflammatory response in
several disorders including autoimmune diseases, type 2 diabetes,
Alzheimer’s disease, atherosclerosis, and autoinflammatory disorders.
“These
findings are important because endogenous metabolites like BHB that
block the NLRP3 inflammasome could be relevant against many
inflammatory diseases, including those where there are mutations in the
NLRP3 genes,” said Vishwa Deep Dixit, professor in the Section of Comparative Medicine at Yale School of Medicine.
BHB
is a metabolite produced by the body in response to fasting,
high-intensity exercise, caloric restriction, or consumption of the
low-carbohydrate ketogenic diet. Dixit said it is well known that
fasting and calorie restriction reduces inflammation in the body, but it
was unclear how immune cells adapt to reduced availability of glucose
and if they can respond to metabolites produced from fat oxidation.
Working
with mice and human immune cells, Dixit and colleagues focused on how
macrophages — specialized immune cells that produce inflammation —
respond when exposed to ketone bodies and whether that impacts the
inflammasone complex.
The team introduced BHB to mouse models of
inflammatory diseases caused by NLP3. They found that this reduced
inflammation, and that inflammation was also reduced when the mice were
given a ketogenic diet, which elevates the levels of BHB in the
bloodstream.
“Our results suggest that the endogenous metabolites
like BHB that are produced during low-carb dieting, fasting, or
high-intensity exercise can lower the NLRP3 inflammasome,” said Dixit.
Other
authors on the study include Yun-Hee Youm, Kim Y. Nguyen, Ryan W Grant,
Emily L. Goldberg, Monica Bodogai, Dongin Kim, Dominic D’Agostino, Noah
Planavsky, Christopher Lupfer, Thirumala D Kanneganti, Seokwon
Kang,
Tamas L. Horvath, Tarek M. Fahmy, Peter A. Crawford, Arya Biragyn,
and Emad Alnemri.
The research was funded in part by National Institutes of Health grants AI105097, AGO43608, AG031797, and DK090556.
Citation: Nature Medicine DOI: 10.1038/nm.3804