Clinical trial NCT06169137: Pilot Study of Isocaloric Time Restricted Eating on Ketone Metabolism and Immunoregulation
Official title: Pilot Study of Isocaloric Time Restricted Eating on Ketone Metabolism and Immunoregulation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Obesity
Body Weight
Keywords: Diet
Time Restricted Eating
Inflammation
Ketone Bodies
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2023-12-13
Enrollment: 150
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Background:

Time restricted eating (TRE) is a form of fasting in which a person eats only during a set window of time, which is usually between 4 and 10 hours each day. Researchers want to know more about how TRE may affect health.

Objective:

To learn how TRE affects women with different body sizes.

Eligibility:

Healthy women aged 18 to 50 years.

Design:

Participants will have 2 visits: 1 screening visit and one 5-day stay in the clinic.

Participants will fast before both visits. They will have a physical exam with blood tests. They will talk to a nutritionist about the foods they eat. They will lay under a clear hood for up to 45 minutes during a test that measures how many calories they burn while resting.

Participants will keep a food diary for up to 7 days before their clinic stay. They will apply a continuous glucose monitor the day before they go to the clinic. This is a device that attaches to the skin of the stomach. They will wear this device throughout their clinic stay.

All meals will be provided during the clinic stay. Participants will follow TRE on 3 days. They will answer survey questions and have tests during their stay, including:

* DXA (dual energy X-ray absorptiometry) scan. Participants will lie on a padded table. Their body will be scanned to measure how much muscle, bone, fat, and other tissues they have.
* Stable isotope tracer study. Small amounts of sugar and other substances will be given through a tube attached to a needle inserted into a vein in the arm. Blood samples will be collected.

Detailed description: Study Description:

Intermittent fasting confers anti-inflammatory effects, although underlying metabolic mechanisms are poorly defined. This pilot study will explore ketone bodies as a mediator of inflammation in response to time restricted eating (TRE-6-hr feeding/18-hr fast) without caloric restriction compared to a more conventional dietary regimen (12-hr feeding/12-hr fast) in women classified as obese and lean.

Objectives:

Primary Aim 1: Quantify ketone body (beta-OHB) whole-body turnover after short-term early 6-hr TRE compared to a conventional 12-hr dietary regimen in women.

Primary Aim 2: Quantify CD4+ T cell responses after short-term early 6-hr TRE compared to a conventional 12-hr dietary regimen in women.

Secondary Aim 1: Determine metabolic response to short-term early 6-hr TRE in lean women vs women with obesity.

Secondary Aim 2: Determine immunomodulatory effects of short-term early 6-hr TRE in lean women vs women with obesity.

Exploratory Aim 1: Evaluate ketone body, hormonal, and cardiometabolic responses after short-term early 6-hr TRE compared to a conventional 12-hr dietary regimen in women classified as lean and with obesity.

Exploratory Aim 2: Evaluate effects of short-term early 6-hr TRE on perceived appetite, stress, and gastrointestinal symptoms.

Endpoints:

Primary:

1. Change from admission day 0 in ketone body (beta-OHB) rate of appearance (Ra) after three days of 6-hr TRE
2. Change from admission in CD4+ T cell responsiveness (Th17 polarization) after three days of 6-hr TRE

Secondary:

1. Change from admission day 0 in post-absorptive glucose Ra quantified using \[6,6-2H2\]glucose (intravenous) after three days 6- hr TRE
2. Change from admission day 0 in ketone body Ra in lean vs. obese women after three days 6-hr TRE
3. CD4+ T cell responsiveness (Th17 polarization) in lean vs. obese women after three days 6-hr TRE
4. Evaluation of ketone biology in isolated CD4+ T cells, using biochemical analysis and analysis of metabolic reprograming at the gene regulatory level

Exploratory:

1. Circulating ketone body concentrations at admission day 0 and after 3 days of TRE
2. Hormonal mediators of metabolic status (morning cortisol, fasting insulin and glucagon/incretins, thyroid hormones, sex hormone binding globulin, anti-mullerian hormone)
3. Cardiometabolic biomarkers (glycemic, lipid, and inflammatory; trimethylamine N-oxide \[TMAO\])
4. Perceived appetite, stress, and gastrointestinal symptom scores

Eligibility criteria: * INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Stated willingness to comply with all study procedures and availability for the duration of the study
2. Women between ages 18-50 years who are premenopausal (defined as regular menses and/or FSH \<ULN)
3. BMI of 18-24.9 or \>=30 kg/m\^2
4. In good general health as evidenced by medical history and/or screening laboratory evaluation.
5. Agreement to adhere to Lifestyle Considerations throughout study duration

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Diagnosis/treatment for immune/inflammatory disorder or other metabolic conditions that would interfere with study parameters, including diabetes, chronic kidney, chronic liver disease, history of hypoglycemia, and thyroid disease (with the exception of chronic controlled hypothyroidism as measured by TSH within normal limits)
2. Current use of antihyperglycemic medications, systemic steroids, adrenergic-stimulating agents, or medications affecting sleep, circadian rhythms, or metabolism which affect parameters under investigation (examples include oral contraceptives, anti-diabetic agents, nicotinamide riboside, tryptophan, vitamin B3 supplements)
3. Caffeine consumption in excess of approximately 300 mg (approximately three 8-oz cups of coffee) daily
4. Factors that affect circadian rhythms including individuals who perform overnight shift work, report irregular sleep and/or eating schedules, and who regularly fast for more than 15 hours/day
5. History of an eating disorder by self-report or medical history
6. Food allergies/intolerances or dietary patterns that would prohibit consumption of metabolic diet
7. Inability to provide informed consent
8. Pregnancy or lactation
9. Unstable weight with more than 5% body weight change in last previous 3 months
10. Engaged in competitive sports training and/ or unwilling to comply with exercise regimen in this protocol.
11. Consumption of more than 3 servings of alcohol daily
12. Current smoker or regular tobacco use, vaping, or other forms of nicotine within prior 3 months

This study will recruit only women. The study design was informed by our Protocol NCT04728165 which investigates an identical 6:18h TRE intervention in males who are healthy and those with psoriasis. Based on our pilot data in men, the current study is needed to test our hypothesis in women. This study in women is a critical next step to replicate the findings in women and to understand sex-specific differences in TRE response and ketone metabolism.

Primary outcomes:
measure: Change in ketone body (beta hydroxybutyrate) rate of appearance (Ra)
timeFrame: Day 0, Day 3
measure: Change in CD4+ T cell responsiveness (Th17 polarization)
timeFrame: Day 0, Day 3
Secondary outcomes:
measure: Change in post-absorptive glucose rate of appearance (Ra)
timeFrame: Day 0, Day 3
measure: Change in ketone body rate of appearance (Ra) in lean women vs women with obesity
timeFrame: Day 0, Day 3
measure: Change in CD4+ T cell responsiveness (Th17 polarization) in lean women vs women with obesity
timeFrame: Day 0, Day 3
measure: Ketone biology in isolated CD4+ T cells
timeFrame: Day 0, Day 3
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Stephanie T Chung, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Han K, Nguyen A, Traba J, Yao X, Kaler M, Huffstutler RD, Levine SJ, Sack MN. A Pilot Study To Investigate the Immune-Modulatory Effects of Fasting in Steroid-Naive Mild Asthmatics. J Immunol. 2018 Sep 1;201(5):1382-1388. doi: 10.4049/jimmunol.1800585. Epub 2018 Jul 18.
citation: Puchalska P, Crawford PA. Metabolic and Signaling Roles of Ketone Bodies in Health and Disease. Annu Rev Nutr. 2021 Oct 11;41:49-77. doi: 10.1146/annurev-nutr-111120-111518.