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Ketone body β-hydroxybutyrate blocks the NLRP3 inflammasome-mediated inflammatory disease
Yun-Hee Youm,1,* Kim Y. Nguyen,1,* Ryan W. Grant,2 Emily L. Goldberg,1 Monica Bodogai,3 Dongin Kim,4 Dominic D'Agostino,5 Noah Planavsky,6 Christopher Lupfer,7 Thirumala D. Kanneganti,7 Seokwon Kang,8 Tamas L. Horvath,1 Tarek M. Fahmy,4 Peter A. Crawford,9 Arya Biragyn,3 Emad Alnemri,8 and Vishwa Deep Dixit
Abstract
Ketone bodies , β-hydroxybutyrate (BHB) and acetoacetate support mammalian survival during states of energy deficit by serving as alternative source of ATP1. BHB levels are elevated during starvation, high-intensity exercise or by the low carbohydrate ketogenic diet2. Prolonged caloric restriction or fasting reduces inflammation as immune system adapts to low glucose supply and energy metabolism switches towards mitochondrial fatty acid oxidation, ketogenesis and ketolysis2-6. However, role of ketones bodies in regulation of innate immune response is unknown. We report that BHB, but neither acetoacetate nor structurally-related short chain fatty acids, butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to several structurally unrelated NLRP3 activators, without impacting NLRC4, AIM2 or non-canonical caspase-11 inflammasome activation. Mechanistically, BHB inhibits NLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 were not dependent on chirality or classical starvation regulated mechanisms like AMPK, reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocked NLRP3 inflammasome without undergoing oxidation in TCA cycle, independently of uncoupling protein-2 (UCP2), Sirt2, receptor Gpr109a and inhibition of NLRP3 did not correlate with magnitude of histone acetylation in macrophages. BHB reduced the NLRP3 inflammasome mediated IL-1β and IL-18 production in human monocytes. In vivo, BHB attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases like Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory syndrome (FCAS) and urate crystal induce body cavity inflammation. Taken together, these findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be mechanistically linked to BHB-mediated inhibition of the NLRP3 inflammasome, and point to the potential use of interventions that elevate circulating BHB against NLRP3-mediated proinflammatory diseases.
A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity
Eric Ravussin,1 Leanne M. Redman,1 James Rochon,2,3 Sai Krupa Das,4 Luigi Fontana,5–7 William E. Kraus,2 Sergei Romashkan,8 Donald A. Williamson,1 Simin N. Meydani,4 Dennis T. Villareal,5 Steven
R. Smith,1,9 Richard I. Stein,5 Tammy M. Scott,4 Tiffany M. Stewart,1 Edward Saltzman,4 Samuel Klein,5 Manju Bhapkar,2 Corby K. Martin,1 Cheryl H. Gilhooly,4 John O. Holloszy,5 Evan C. Hadley,8 and
Susan B. Roberts4; for the CALERIE Study Group*
Abstract
Background. Caloric restriction (CR), energy intake reduced below ad libitum (AL) intake, increases life span in many species. The implications for humans can be clarified by randomized controlled trials of CR.
Methods. To determine CR’s feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21–51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. Outcomes were change from baseline resting metabolic rate adjusted for weight change (“RMR residual”) and core temperature (primary); plasma triiodothyronine (T3) and tumor necrosis factor-α (secondary); and exploratory physiological and psychological measures.
Results. Body mass index averaged 25.1 (range: 21.9–28.0 kg/m2). Eighty-two percent of CR and 95% of AL participants completed the protocol. The CR group achieved 11.7 ± 0.7 %CR (mean ± standard error) and maintained 10.4 ± 0.4% weight loss. Weight change in AL was negligible. RMR residual decreased significantly more in CR than AL at 12 months (p = .04) but not 24 months (M24). Core temperature change differed little between groups. T3 decreased more in CR at M12 and M24 (p < .001), while tumor necrosis factor-α decreased significantly more only at M24 (p = .02). CR had larger decreases in cardiometabolic risk factors and in daily energy expenditure adjusted for weight change, without adverse effects on quality of life. Conclusions. Sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.
Effects of prolonged calorie restriction on inflammation and immune function: a randomized controlled trial in non-obese humans (40.4)
Simin Meydani2, Sai Das2, Carl Piper1, Michael Lewis4, Vishwadeep Dixit3, Alok Gupta3, Dennis Villareal5, Samuel Klein5, Manjushri Bhapkar1, Megan Huang1, Paul Fuss2, Susan Roberts2, John Holloszy5 and Luigi Fontana5
Abstract
Calorie restriction (CR) is shown to improve inflammatory and immune responses and extend life in animals; however, the effect of prolonged CR in humans has not been studied. CALERIE is a multi-center randomized controlled trial, which evaluated the impact of 2 y of 25% CR on key biological functions. As part of the CALERIE we determined the impact of CR on immune and INFL markers of 218 healthy adults aged 21-50 y with BMI of 22- 29 kg/m2. Participants were allocated in a 2:1 ratio to 25% CR or ad-libitum (AL) diets. Serum markers of inflammation (CRP, TNFα, IL-6, IL-8, ICAM-1, MCP-1), as well as WBC counts (total and subset), and antibody response to hepatitis A, tetanus/diphtheria, and pneumococcal vaccines were measured at baseline and after 1 and 2 y of CR. CR significantly reduced CRP and TNFα relative to AL at 24 mo. The estimated change from baseline to 24 mo was -0.65 vs. -0.023 μg/mL for CRP (p=0.012 for group effect), and -0.77 vs. -0.38 pg/mL for TNFα (p=0.025 for group effect). No significant effect was observed for other inflammatory markers. In addition, CR was associated with a small, but significantly lower number of WBC, lymphocytes, and monocytes. There was no significant effect of CR on DTH or response to vaccines. These results suggest that 2 y of CR may reduce key indicators of inflammation, but has only a small or negligible impact on cell mediated immunity.
Here's how dieting and fasting can help ward off Alzheimer's, diabetes
A new research has revealed the anti-inflammatory mechanism of dieting and fasting. 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.
The researchers described how the compound Beta-hydroxybutyrate (BHB) directly inhibits NLRP3, which is part of a complex set of proteins called the inflammasome that drives the inflammatory response in several disorders including autoimmune diseases, type 2 diabetes, Alzheimer's disease, atherosclerosis, and autoinflammatory disorders.
Researcher Vishwa Deep Dixit said that 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.
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.
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.
The 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, added Dixit. The study is published online in Nature Medicine.