Pilot Study of Isocaloric Time Restricted Eating on Ketone Metabolism and Immunoregulation

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.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Body Weight
• Intervention / Treatment: Behavioral: Early Time-Restricted Eating; Behavioral: Conventional dietary regimen (12-hr, 9:30a-9:30p)

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

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stephanie T Chung, M.D.; Phone Number: (240) 479-8137; Email: stephanie.chung@nih.gov
• Study Contact Backup: Name: Lilian S Mabundo; Phone Number: (240) 383-9379; Email: lilian.mabundo@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 800-411-1222; Email: ccopr@nih.gov
      • Contact: Stephanie Chung, M.D.; Phone Number: (240) 479-8137; Email: stephanie.chung@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Premenopausal women (lean and obese); Ages 18-50 yearsBMI 18.0-24.5 mg/k^2 or BMI > 30 mg/k^2	Behavioral: Early Time-Restricted Eating; Participants will be provided all meals to consume within a 6-hour timeframe (9:30-3:30p); Behavioral: Conventional dietary regimen (12-hr, 9:30a-9:30p); Participants will be provided all meals to consume within a 12-hour timeframe (9:30a-9:30p)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CD4+ T cell responsiveness (Th17 polarization)	Within subject difference in CD4+ T cell response after 3 days of 6-hr TRE compared to a 12-hr eating window regimen	Day 0, Day 3
Change in ketone body (beta hydroxybutyrate) rate of appearance (Ra)	Within subject difference in ketone body (beta hydroxybutyrate) rate of appearance (Ra) after 3 days of 6-hr TRE compared to a 12-hr eating window regimen	Day 0, Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in post-absorptive glucose rate of appearance (Ra)	Within subjective difference in glucose Ra quantified using [6,6- 2H2]glucose (intravenous) after 3 days of 6-hr TRE compared to a 12-hr eating window regimen	Day 0, Day 3
Change in ketone body rate of appearance (Ra) in lean women vs women with obesity	Between subject comparison in ketone body rate of appearance after 3 days of 6-hr TRE compared to a 12-hr eating window regimen in lean women vs women with obesity	Day 0, Day 3
Change in CD4+ T cell responsiveness (Th17 polarization) in lean women vs women with obesity	Between subject comparison in CD4+ T cell response after 3 days of 6-hr TRE compared to a 12-hr eating window regimen in lean women vs women with obesity	Day 0, Day 3
Ketone biology in isolated CD4+ T cells	Biochemical and metabolic reprogramming analysis at the gene regulatory level	Day 0, Day 3

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Stephanie T Chung, M.D., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• 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.
• 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.
• Thota GP, Macheret NA, Glaros SB, Kacker IN, Cantor SL, Mabundo L, Malandrino N, Chen KY, Courville AB, Turner S, Yang S, Krenek A, Recupero TC, Klein RJ, Han K, Puchalska P, Crawford P, Sack MN, Chung ST. Effects of Time-Restricted Eating on Ketone Metabolism and Immunoregulation in Premenopausal Women: Protocol for a Pilot, Prospective, Single-Arm Dietary Intervention Study. JMIR Res Protoc. 2026 Mar 6;15:e81063. doi: 10.2196/81063.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2024
• Primary Completion (Estimated): February 5, 2027
• Study Completion (Estimated): February 5, 2027

Study Registration Dates

• First Submitted: December 11, 2023
• First Submitted That Met QC Criteria: December 11, 2023
• First Posted (Actual): December 13, 2023

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 9, 2026
• Last Verified: May 8, 2026

More Information

Terms related to this study

• Keywords: Inflammation; Diet; Time Restricted Eating; Ketone Bodies
• Additional Relevant MeSH Terms: Pathologic Processes; Nutrition Disorders; Overnutrition; Overweight; Pathological Conditions, Signs and Symptoms; Behavior; Nutritional and Metabolic Diseases; Signs and Symptoms; Feeding Behavior; Fasting; Obesity; Body Weight; Inflammation; Intermittent Fasting
• Other Study ID Numbers: 10001746; 001746-DK

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators will provide raw data (without identifying information) to journals or other researchers upon request.
• IPD Sharing Time Frame: The data will be provided upon request within 1 year after publication and will be available to indefinitely
• IPD Sharing Access Criteria: The PI will accept requests from other researchers who are examining pertinent outcomes
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No