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

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:

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

Secondary:

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

Exploratory:

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

• INCLUSION CRITERIA:

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

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

• 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)
• 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)
• Caffeine consumption in excess of approximately 300 mg (approximately three 8-oz cups of coffee) daily
• 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
• History of an eating disorder by self-report or medical history
• Food allergies/intolerances or dietary patterns that would prohibit consumption of metabolic diet
• Inability to provide informed consent
• Pregnancy or lactation
• Unstable weight with more than 5% body weight change in last previous 3 months
• Engaged in competitive sports training and/ or unwilling to comply with exercise regimen in this protocol.
• Consumption of more than 3 servings of alcohol daily
• 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.