Prolonged Daily Fasting as a Viable Alternative to Caloric Restriction in At-Risk Obese Humans

Study Overview
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Brief Summary
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Purpose: Obesity is reaching epidemic proportions, affecting 36% of the adult population in the United States. There is intense interest in dietary management to treat obesity and its associated complications. The first line of obesity treatment is caloric restriction (CR), although recidivism is common. For moderate CR, attrition rates of 20% are often reported, therefore weight loss options beyond CR are urgently needed.

Detailed Description
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Aim#1: Evaluate the effect of TRE with ad libitum intake on weight and body composition. H 1.1: Individuals in the TRE and CR groups will have similar weight loss, which will be greater than weight loss achieved in the non-TRE group (primary outcome). H 1.2: TRE will result in greater loss of loss of total body fat (quantified by DXA) and greater loss of hepatic/visceral fat/ectopic fat (quantified by MRI) than CR. Aim#2: Assess the effect of TRE with ad libitum intake on caloric balance. H 2.1: TRE will reduce caloric intake compared with non-TRE [gold-standard interviewer administered 24-hour dietary recall (primary outcome)] with similar reduction as with CR, H.2.2: Compared with non-TRE, TRE will result in selection of more nutrient dense foods during a supervised meal within their eating window; this selection will be similar to CR. H 2.3 TRE will not alter physical activity, but will increase fat oxidation compared with CR and non-TRE. Aim#3: Assess the effect of TRE with ad libitum intake on metabolic flexibility. H 3.1: TRE will enhance metabolic flexibility compared with CR and non-TRE as measured by indirect calorimetry [RQ:Respiratory quotient before and during 2 step 6,6-2H2 hyperinsulinemic-euglycemic clamp: primary outcome]. H 3.2: TRE will improve insulin sensitivity compared with non-TRE and similar to CR. H 3.3: TRE will augment greater fasting lipolysis compared to CR and non-TRE as measured by [U-13C] palmitate and enhance lipolysis suppression during the 2 step 6,6-2H2 hyperinsulinemic-euglycemic clamp. If these hypotheses are confirmed, this project has significant impact. First, it will advance understanding of the mechanisms underpinning this innovative intervention. Second, TRE can be a practical means of implementing prolonged fasting on a large scale, thereby transforming the treatment of obesity. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1-TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Official Title
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Prolonged Daily Fasting as a Viable Alternative to Caloric Restriction in At-Risk Obese Humans

Conditions
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Obesity

Intervention / Treatment
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* Behavioral: Time Restricted Eating (TRE)
* Behavioral: Caloric Restriction (CR)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI ≥30 and ≤ 55 kg/m^2 Own a smartphone compatible with the myCircadianClock (mCC) phone application Self-reported habitual wakening between 5-9 am Self reported sleep duration of 6-9 hours Weight must be stable [+/- 5 pounds] for at least 3 months prior to the study Eating window (time between 1st food intake and last food take) ≥14 hours using mCC Insulin resistance based on HOMA-IR≥ 2.5 from screening visit results Able to understand English Exclusion Criteria: Use of beta-blockers or medications known to affect weight, such as thiazolidinedione (TZD), insulin, glucagon-like peptide (GLP)-1 agonists, phentermine, or sibutamine Shift work (i.e. working from 11pm to 7am) Clinically significant medical issues (diabetes, cardiovascular disease, uncontrolled pulmonary disease) A history of abnormal laboratory results, such as hematologic (platelets < 100), hepatic (LFTs > 2X nl), renal (Cr > 1.5) MRI contraindication (metal in body, claustrophobia) Eating window < 12 hours per day Unable to consistently document food intake using the mCC app (need at least 2 eating occasions> 6 hours apart on a given day for at least 50% of days) Pregnancy Illiteracy Concern for active eating disorder per screening questionnaire Self-reported eating disorder or history of eating disorder

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Time Restricted Eating (TRE)<br>For the TRE group, we will restrict the eating window to 8 hours, where they will eat ad libitum. This is the same interval established by Dr. Panda and by our preliminary data. This interval will be entered into the mCC app and participants will be asked to adhere to this eating window during the intervention. All eating occasions will be logged using the mCC app. Only water and medications will be allowed outside of the eating window. | Behavioral: Time Restricted Eating (TRE)<br>* daily eating window restricted to 8 hours<br>|
| Active Comparator: Caloric Restriction (CR)<br>Participants randomized to CR will meet with the study dietitian prior to the intervention and be counseled on options to reduce their caloric intake by 15%, while maintaining their eating window. The 15% reduction was selected as our preliminary data and recent literature suggest that TRE with ad libitum intake reduces caloric intake by  270 to 300 cal/day. The 15% CR is similar to the 11.9% CR achieved by the CALERIE-2 study, which is a 2 year study of CR.26 All eating occasions will be logged using the mCC app. The weekly dietitian review of the mCC information will include maintenance of the eating window and examination of dietary intake to determine compliance with the 15% CR. | Behavioral: Caloric Restriction (CR)<br>* 15% daily caloric deficient<br>|
| No Intervention: Unrestricted Eating (non-TRE)<br>For the unrestricted eating (non-TRE) group, participants will eat ad libitum per their usual habits. They will receive initial counseling about mCC logging. All eating occasions will be logged using the mCC app. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Weight | Weight will be measured by standard scale and reported in kilograms. | Baseline, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Whole Body Percent Fat | Body composition will be measured by dual energy x-ray absorptometry (DXA). Parameters of body composition will be calculated by integrated DXA software. Whole body percent fat will be reported as a percentage. | Baseline, 12 weeks | 
| Change in Visceral Fat | Body composition will be measured by dual energy x-ray absorptometry (DXA). Parameters of body composition will be calculated by integrated DXA software. Visceral fat will be reported in grams. | Baseline, 12 weeks | 
| Change in Lean Mass | Body composition will be measured by dual energy x-ray absorptometry (DXA). Parameters of body composition will be calculated by integrated DXA software. Lean mass will be reported in kilograms. | Baseline, 12 weeks | 
| Change in Fat Mass | Body composition will be measured by dual energy x-ray absorptometry (DXA). Parameters of body composition will be calculated by integrated DXA software. Fat mass will be reported in kilograms. | Baseline, 12 weeks | 
| Change in Caloric Intake | Two interviewer-administered 24-hour dietary recalls will be collected from each participant at baseline and 12 weeks. The recalls will be conducted over the telephone and will be unannounced to minimize measurement reactivity. Diet data will be collected using the Nutrition Data System for Research (NDSR) to calculate Calories. Calories will be averaged across the 2 recalls at each time point. Outcome will be reported as difference between average caloric intake at baseline and 12 weeks. Outcome will be reported in kilocalories (Calories). | Baseline, 12 weeks | 
| Change in metabolic flexibility | indirect calorimetry to measure glucose and fat oxidation for   30 minutes before and at the end of the 2 step 4-hour hyperinsulinemic-euglycemic clamp [low-dose (10 mU/m2/min) insulin infusion for 2 hours, high-dose (40 mU/m2/min) insulin infusion for 2 hours] Fluctuations in VO2 and VCO2 in the first 5-10 minutes of data acquisition were removed and the mean VO2 and VCO2 at steady state was used for data analysis. The respiratory exchange ratio (RER) was calculated by VCO2 / VO2. . Metabolic flexibility was calculated by the RERclamp-RERrest | baseline, 12 weeks |