Clinical trial NCT02122575: Effect of Fasting on the NLRP3 Inflammasome
Official title: Pilot Study to Evaluate the Effect of Fasting on the NLRP3 Inflammasome
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cardiovascular Disease
Inflammatory Disease
Keywords: Inflammasome
Fasting
Sirt3
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2014-04-24
Enrollment: 23
Sex: ALL
Minimum age (years): 21
Maximum age (years): 37
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: -Males and females between the ages of 21 and 37@@@-BMI between 23.5 and 29

Brief summary: Background:

- Restricting calories can help a person reduce risk factors for heart disease. Researchers have found that not eating or drinking anything but water for 24 hours prevents the activation of a component of the immune system, called the inflammasome. The inflammasome is associated with the development of diabetes and heart disease. Researchers want to learn more about the body s response to fasting.

Objective:

- To explore the benefits of calorie restriction on heart health.

Eligibility:

- Healthy adults ages 21 32 with a body mass index between 26 and 29.

Design:

* Participants will be screened with a medical history, physical exam and blood test.
* Participants will not eat or drink after 10 p.m. before their first visit.
* Participants have breakfast at the clinic. The breakfast will be about 500 calories. Then they will not eat or drink (except water) for 24 hours.
* Participants will return to the clinic the next morning. They will have blood drawn. Then they will have breakfast. Blood will be drawn again at 1 hour and 3 hours after the meal.
* Blood and urine tests at the end of the fast and following the meals will be done to confirm that participants have fasted for the full 24-hour period.

Detailed description: A caloric restricted diet has numerous health effects including the reduction in numerous cardiovascular disease risk factors. The cellular programs activated by caloric restriction are similarly turned on in preclinical studies in response to a 24-hour fast. We have found that a beneficial effect of a 24-hour fasting blunts the activation of a component of the immune system, termed the inflammasome, which is associated with the development of diabetes and atherosclerosis. We would like to study the inflammasome in human blood cells to evaluate whether the beneficial immune effects of fasting/caloric restriction are operational in humans. Blood samples to test the immune response will be collected in subjects after a fixed caloric meal and in response to a 24-hour fast (water intake will not be restricted). The objective of this pilot study is to identify if these immune adaptive pathways can be activated in human subjects as a possible readout to test whether this pathway could be investigated as a therapeutic target to blunt/negate the inflammation associated with nutrient-excess associated diseases such as diabetes and/or atherosclerosis.

Eligibility criteria: * INCLUSION CRITERIA:

As this is a pilot study, the age-range and BMI range of subjects will be restricted to potentially reduce metabolic variables associated with a wide age- and BMI-range.

* Males and females between the ages of 21 and 37
* BMI between 23.5 and 29

EXCLUSION CRITERIA:

* Subjects with an acute or chronic illness as per history, on laboratory analysis or due to use of medications
* Subjects taking vitamins or supplements or any medications, except oral contraceptives within 4 weeks of participation into this study.
* BMI \<23.5 or \>29
* Female subjects who are pregnant or lactating
* Subjects who have donated blood or participated in another clinical trial involving blood draws in the last 8 weeks.
* Subjects who use nicotine products

Primary outcomes:
measure: Determine whether the NLRP3 inflammasome is blunted by a 24 hours fast in PBMC's from normal volunteers.
timeFrame: 24 hours
Secondary outcomes:
measure: Evaluate whether these effects are associated with activation of the Sirt3 and its canonical mitochondrial adaptive programs.
timeFrame: end of study
measure: Determine whether serum from subjects in fasted state will blunt the inflammasome compared to serum from the fed stat in a human transformed macrophage cell line.
timeFrame: end of study
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Michael N Sack, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012 Mar 6;18(3):363-74. doi: 10.1038/nm.2627.
citation: Haneklaus M, Gerlic M, Kurowska-Stolarska M, Rainey AA, Pich D, McInnes IB, Hammerschmidt W, O'Neill LA, Masters SL. Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1beta production. J Immunol. 2012 Oct 15;189(8):3795-9. doi: 10.4049/jimmunol.1200312. Epub 2012 Sep 14.
citation: Fontana L, Meyer TE, Klein S, Holloszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6659-63. doi: 10.1073/pnas.0308291101. Epub 2004 Apr 19.
citation: Traba J, Kwarteng-Siaw M, Okoli TC, Li J, Huffstutler RD, Bray A, Waclawiw MA, Han K, Pelletier M, Sauve AA, Siegel RM, Sack MN. Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects. J Clin Invest. 2015 Nov 3;125(12):4592-600. doi: 10.1172/JCI83260.