Time-Restricted Eating, Exercise and Cardiometabolic Health in Obesity

Study Overview
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Brief Summary
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In Spain, overweight and obesity prevalence is reaching 70% in men and 50% in women. Excess of triglycerides are usually stored in the subcutaneous adipose tissue (SAT), until a point where SAT is unable to expand further. Therefore, lipids are deposited in visceral and other peripheral organs and tissues that are not otherwise designed for adipose storage such as the liver, pancreas or the skeletal muscle, a process known as ectopic fat deposition. Time-restricted eating (TRE) is a recently emerged intermittent fasting approach which has the potential to maximize the beneficial metabolic effects extensively reported for energy intake restriction. Furthermore, exercise reduces hepatic steatosis and improves cardiometabolic health in humans. However, whether the effects of TRE combined with exercise on reducing hepatic steatosis are superior to TRE or exercise intervention alone remains unknown. The TEMPUS study will investigate the effects of a 12-week TRE combined with supervised exercise intervention, as compared with TRE or exercise alone, and usual-care control group, on hepatic fat (primary outcome) and cardiometabolic health (secondary outcomes) in adults with obesity; and to unveil the role of gut microbiota.

Official Title
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Impact of Time-Restricted Eating and Supervised Exercise on Hepatic Steatosis and Cardiometabolic Health in Adults With Obesity

Conditions
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Obesity, Time Restricted Feeding, Exercise, Hepatic Steatosis, Cardiometabolic Syndrome

Intervention / Treatment
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* Behavioral: Time-restricted eating intervention
* Behavioral: Exercise intervention
* Behavioral: Time-restricted eating plus exercise intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 25-65 years. Body mass index ≥28.0 and <40.0 kg/m2. Weight stability (within 5% of screening weight) for >3 months prior to study entry. Habitual eating window ≥11 hours. Exclusion Criteria: History of a major adverse cardiovascular event, clinically significant kidney, endocrine, or neurological disease, bariatric surgery, HIV/AIDS, known inflammatory and/or rheumatologic disease, cancer, or other medical condition in which fasting or exercise is contraindicated. Type 1 or Type 2 diabetes. Major psychiatric disorders, eating disorders, sleep disorders, or alcohol abuse. Regular use of medication or compounds that may affect study outcomes (e.g., antidiabetic, steroids, beta-blockers, antibiotics, prebiotics, probiotics and symbiotics). Participating in a weight loss, a weight-management program or a supervised exercise program (more than 30 minutes three times per week, or 45 minutes twice a week, moderate/vigorous intensity). Pregnancy and lactation or planned pregnancy (within the study period). Caregiver for a dependent requiring frequent nocturnal care/sleep interruptions. Shift workers with variable hours (e.g., nocturnal). Frequent travel over time zones during the study period. Fear of needles and claustrophobia to magnetic resonance imaging (MRI). Being unable to understand and to accept the instructions or the study objectives and protocol.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Time-restricted eating intervention<br>Participants will be asked to reduce their daily eating time window to a maximum of 8 hours/day. They can choose when to begin their eating window but will be advised that the last meal should be completed before or at 20:00 hours. No calorie-containing food or beverage intake will be allowed outside the 8 hours eating window. | Behavioral: Time-restricted eating intervention<br>* Participants will be asked to reduce their daily eating time window to a maximum of 8 hours/day. They can choose when to begin their eating window but will be advised that the last meal should be completed before or at 20:00 hours. No calorie-containing food or beverage intake will be allowed outside the 8 hours eating window.<br>|
| Experimental: Supervised exercise intervention<br>The exercise intervention will include 2 days/week of supervised moderate-high intensity resistance training (rating perceived exertion >7, circuit-training, upper and lower body exercises involving major muscle groups) and high-intensity interval training (4 sets of 4-minute intervals at >85% peak heat rate with 4-minute of active recovery at 50-65% peak heat rate, uphill treadmill walking). Moreover, participants will receive an individualized moderate-intensity goal-setting aerobic (walking) program consisting of increasing 15% daily steps per week. | Behavioral: Exercise intervention<br>* The exercise intervention will include 2 days/week of supervised moderate-high intensity resistance training (rating perceived exertion >7, circuit-training, upper and lower body exercises involving major muscle groups) and high-intensity interval training (4 sets of 4-minute intervals at >85% peak heat rate with 4-minute of active recovery at 50-65% peak heat rate, uphill treadmill walking). This intervention has already been tested previously in our lab. Moreover, participants will receive an individualized moderate-intensity goal-setting aerobic (walking) program consisting of increasing 15% daily steps per week.<br>|
| No Intervention: Usual-care control group<br>Participants will receive standard recommendations on healthy lifestyle based on Mediterranean dietary pattern and physical activity recommendations for weight loss and health promotion. | |
| Experimental: Time-restricted eating plus Supervised exercise<br>Participants will be asked to reduce their daily eating time window to a maximum of 8 hours/day. They can choose when to begin their eating window but will be advised that the last meal should be completed before or at 20:00 hours. No calorie-containing food or beverage intake will be allowed outside the 8 hours eating window. The exercise intervention will include 2 days/week of supervised moderate-high intensity resistance training (rating perceived exertion >7, circuit-training, upper and lower body exercises involving major muscle groups) and high-intensity interval training (4 sets of 4-minute intervals at >85% peak heat rate with 4-minute of active recovery at 50-65% peak heat rate, uphill treadmill walking). Moreover, participants will receive an individualized moderate-intensity goal- | Behavioral: Time-restricted eating plus exercise intervention<br>* Participants will be asked to reduce their daily eating time window to a maximum of 8 hours/day. They can choose when to begin their eating window but will be advised that the last meal should be completed before or at 20:00 hours. No calorie-containing food or beverage intake will be allowed outside the 8 hours eating window. The exercise intervention will include 2 days/week of supervised moderate-high intensity resistance training (rating perceived exertion >7, circuit-training, upper and lower body exercises involving major muscle groups) and high-intensity interval training (4 sets of 4-minute intervals at >85% peak heat rate with 4-minute of active recovery at 50-65% peak heat rate, uphill treadmill walking). This intervention has already been tested previously in our lab. Moreover, participants will receive an individualized moderate-intensity goal-setting aerobic (walking) program consisting of increasing 15% daily steps per week.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hepatic fat content | Hepatic fat content will be assessed by Magnetic Resonance Imaging (MRI) | Change from baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hepatic elasticity | Viscosity, fibrosis severity and steatosis will be assessed by US elastography | Change from baseline to 12 weeks | 
| Change in values of alkaline phosphatase | Fasting blood samples will be used to asses alkaline phosphatase | Change from baseline to 12 weeks | 
| Change in values of alanine transaminase | Fasting blood samples will be used to asses alanine transaminase | Change from baseline to 12 weeks | 
| Change in values of gamma-glutamyl transferase | Fasting blood samples will be used to assess gamma-glutamyl transferase | Change from baseline to 12 weeks | 
| Change in values of Vitamin D | Fasting blood samples will be used to assess Vitamin D | Change from baseline to 12 weeks | 
| Change in values of Calcium | Fasting blood samples will be used to assess Calcium | Change from baseline to 12 weeks | 
| Change in values of Bilrubin | Fasting blood samples will be used to assess Bilrubin | Change from baseline to 12 weeks | 
| Change in values of glomerular filtration rate | Fasting blood samples will be used to assess glomerular filtration rate | Change from baseline to 12 weeks | 
| Change in values of estradiol | Fasting blood samples will be used to assess estradiol | Change from baseline to 12 weeks | 
| Change in values of progesterone | Fasting blood samples will be used to assess progesterone | Change from baseline to 12 weeks | 
| Change in values of testosterone | Fasting blood samples will be used to assess testosterone | Change from baseline to 12 weeks | 
| Change in values of follicle stimulating hormone | Fasting blood samples will be used to assess follicle stimulating hormone | Change from baseline to 12 weeks | 
| Change in values of luteinizing hormone | Fasting blood samples will be used to assess luteinizing hormone | Change from baseline to 12 weeks | 
| Change in values of thyrotropin | Fasting blood samples will be used to assess thyrotropin | Change from baseline to 12 weeks | 
| Change in values of thyroxine | Fasting blood samples will be used to assess thyroxine | Change from baseline to 12 weeks | 
| Change in values of triiodothyronine | Fasting blood samples will be used to assess triiodothyronine | Change from baseline to 12 weeks | 
| Change in visceral adipose tissue | Visceral adipose tissue will be assessed by Magnetic Resonance Imaging (MRI) | Change from baseline to 12 weeks | 
| Change in abdominal subcutaneous adipose tissue | Abdominal subcutaneous adipose tissue will be assessed by Magnetic Resonance Imaging (MRI) | Change from baseline to 12 weeks | 
| Change in visceral adipose tissue | Visceral adipose tissue will be assessed by Magnetic Resonance Imaging (MRI) | Change from 12 weeks of intervention to 12 months | 
| Change in abdominal subcutaneous adipose tissue | Abdominal subcutaneous adipose tissue will be assessed by Magnetic Resonance Imaging (MRI) | Change from 12 weeks of intervention to 12 months | 
| Change in pancreatic fat content | Pancreatic fat content will be assessed by Magnetic Resonance Imaging (MRI) | Change from baseline to 12 weeks | 
| Change in pancreatic fat content | Pancreatic fat content will be assessed by Magnetic Resonance Imaging (MRI) | Change from 12 weeks of intervention to 12 months | 
| Change in intramuscular fat content | Intramuscular fat content will be assessed by Magnetic Resonance Imaging (MRI) | Change from baseline to 12 weeks | 
| Change in intramuscular fat content | Intramuscular fat content will be assessed by Magnetic Resonance Imaging (MRI) | Change from 12 weeks of intervention to 12 months | 
| Change in values of fasting glucose | Fasting blood samples will be used to assess glucose | Change from baseline to 12 weeks | 
| Change in HOMA-IR index. | Fasting blood samples will be used to assess glucose and insuline and HOMA index will be computed | Change from baseline to 12 weeks | 
| Change in values of HbA1c | Fasting blood samples will be used to assess HbA1c | Change from baseline to 12 weeks | 
| Change in values of fasting triglycerides | Fasting blood samples will be used to assess levels of triglycerides | Change from baseline to 12 weeks | 
| Change in values of fasting high-density lipoprotein cholesterol | Fasting blood samples will be used to assess levels of high-density lipoprotein cholesterol | Change from baseline to 12 weeks | 
| Change in values of fasting low-density lipoprotein cholesterol | Fasting blood samples will be used to assess levels of low-density lipoprotein cholesterol | Change from baseline to 12 weeks | 
| Change in values of fasting total cholesterol | Fasting blood samples will be used to assess levels of total cholesterol | Change from baseline to 12 weeks | 
| Change in values of C-reactive protein | Fasting blood samples will be used to assess levels of C-reactive protein | Change from baseline to 12 weeks | 
| Change in values of interleukin 6 | Fasting blood samples will be used to assess levels of interleukin 6 | Change from baseline to 12 weeks | 
| Change in values of creatinine | Fasting blood samples will be used to assess levels of creatinine | Change from baseline to 12 weeks | 
| Change in values of creatine kinase | Fasting blood samples will be used to assess levels of creatine kinase | Change from baseline to 12 weeks | 
| Change in values of iron | Fasting blood samples will be used to assess levels of iron | Change from baseline to 12 weeks | 
| Change in values of ferritin | Fasting blood samples will be used to assess levels of ferritin | Change from baseline to 12 weeks | 
| Change in values of folic acid | Fasting blood samples will be used to assess levels of folic acid | Change from baseline to 12 weeks | 
| Change in values of apolipoprotein A1 | Fasting blood samples will be used to assess levels of apolipoprotein A1 | Change from baseline to 12 weeks | 
| Change in values of apolipoprotein B | Fasting blood samples will be used to assess levels of apolipoprotein B | Change from baseline to 12 weeks | 
| Change in levels of mean glucose (Continuous Glucose Monitoring) | Men glucose over 14 days will be assessed by Continuous Glucose Monitoring during 2 weeks | Change from baseline to the last 2 weeks of intervention | 
| Change in quantitative insulin-sensitivity check index | Quantitative insulin-sensitivity check index will be assessed by oral glucose tolerance test | Change from baseline to the last 2 weeks of intervention | 
| Change in Body weight | Body weight will be measured by a digital scale | Change from baseline to 12 weeks | 
| Change in Body weight | Body weight will be measured by a digital scale | Change from 12 weeks of intervention to 12 months | 
| Change in Body height | Body height will be measured by a stadiometer | Change from baseline to 12 weeks | 
| Change in Body height | Body height will be measured by a stadiometer | Change from 12 weeks of intervention to 12 months | 
| Change in fat mass | Fat mass will be assessed by Dual-energy X-ray Absorptiometry (DXA) | Change from baseline to 12 weeks | 
| Change in fat free mass | Fat free mass will be assessed by Dual-energy X-ray Absorptiometry (DXA) | Change from baseline to 12 weeks | 
| Change in bone mineral density | Bone mineral density will be assessed by Dual-energy X-ray Absorptiometry (DXA) | Change from baseline to 12 weeks | 
| Change in fat mass | Fat mass will be assessed by Dual-energy X-ray Absorptiometry (DXA) | Change from 12 weeks of intervention to 12 months | 
| Change in fat free mass | Fat free mass will be assessed by Dual-energy X-ray Absorptiometry (DXA) | Change from 12 weeks of intervention to 12 months | 
| Change in bone mineral density | Bone mineral density will be assessed by Dual-energy X-ray Absorptiometry (DXA) | Change from 12 weeks of intervention to 12 months | 
| Change in waist circumference | Waist circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry | Change from baseline to 12 weeks | 
| Change in calf girth | Calf girth will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry | Change from baseline to 12 weeks | 
| Change in waist circumference | Waist circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry | Change from 12 weeks of intervention to 12 months | 
| Change in calf girth | Calf girth will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry | Change from 12 weeks of intervention to 12 months | 
| Change in hip circumference | Hip circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry | Change from baseline to 12 weeks | 
| Change in hip circumference | Hip circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry | Change from 12 weeks of intervention to 12 months | 
| Change in neck circumference | Neck circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry | Change from baseline to 12 weeks | 
| Change in neck circumference | Neck circumference will be assessed by measuring tape following the procedures outlined by the International Society for the Advancement of Kinanthropometry | Change from 12 weeks of intervention to 12 months | 
| Change in systolic blood pressure | Systolic blood pressure will be assessed by blood pressure monitor | Change from baseline to 12 weeks | 
| Change in systolic blood pressure | Systolic blood pressure will be assessed by blood pressure monitor | Change from 12 weeks of intervention to 12 months | 
| Change in diastolic blood pressure | Diastolic blood pressure will be assessed by blood pressure monitor | Change from baseline to 12 weeks | 
| Change in diastolic blood pressure | Diastolic blood pressure will be assessed by blood pressure monitor | Change from 12 weeks of intervention to 12 months | 
| Change in energy intake | Energy intake (kcal/day) will be assessed by 24h recalls | Change from baseline to 12 weeks | 
| Change in carbohydrates intake | Macronutrients intake (g/day and percentage of energy intake) will be assessed by 24h recalls | Change from baseline to 12 weeks | 
| Change in fat intake | Fat intake (g/day and percentage of energy intake) will be assessed by 24h recalls | Change from baseline to 12 weeks | 
| Change in protein intake | Protein intake (g/day and percentage of energy intake) will be assessed by 24h recalls | Change from baseline to 12 weeks | 
| Change in dietary habits | Dietary habits will be assessed by food frequency questionnaire (FFQ). Minimum value is 1 (never) and maximum value is 9 (more than 6 times per day). Higher values mean a more frequency of a certain food consumption. | Change from baseline to 12 weeks | 
| Change in Appetite traits | Appetite traits will be assessed by the Adult Eating Behavior Questionnaire (AEBQ). Minimum value is 1 (completely disagree) and maximum value is 5 (completely agree). Higher values mean a worse outcome. | Change from baseline to 12 weeks | 
| Change in Subjective sleep quality | Subjective sleep quality will be assessed by the Pittsburgh Sleep Quality Index (PSQI). Minimum value is 0 (never) and maximum value is 3 (3 or more times per week). Higher values mean a worse outcome. | Change from baseline to 12 weeks | 
| Change in Objectively sleep quality | Objectively sleep quality will be assessed by accelerometry | Change from baseline to 12 weeks | 
| Change in Chronotype | Chronotype will be assessed by the Munich Chronotype Questionnaire (MCTQ). | Change from baseline to 12 weeks | 
| Change in Morning-Evening type | Morning-Evening type will be assessed by the Morningness-Eveningness Questionnaire Self-Assessment Version. Define if a person is more morningness or eveningness based on daily times preferences. | Change from baseline to 12 weeks | 
| Change Objectively moderate to vigorous physical activity levels | Objectively physical activity levels will be assessed by accelerometry | Change from baseline to 12 weeks | 
| Change in Depression aspects | Depression aspects will be assessed by the Beck Depression Inventory Fast Screen (BDI-FS). Values ranged from 0 to 63. Higher values mean worse outcome. | Change from baseline to 12 weeks | 
| Change in Stress aspects | Stress aspects will be assessed by the Perceived Stress Scale (PSS). Values ranged from 0 to 40. Higher values mean worse outcome. | Change from baseline to 12 weeks | 
| Change in Anxiety aspects | Anxiety aspects will be assessed by the State-Trait Anxiety Inventory (STAI). Values ranged from 0 to 60. Higher values mean worse outcome. | Change from baseline to 12 weeks | 
| Change in General health | General health will be assessed by the EuroQol 5 dimensions 5 levels (EQ-5D-5L). Values ranged from 0 to 100. Higher values mean better outcome. | Change from baseline to 12 weeks | 
| Change in Quality of life | Quality of life will be assessed by the Rand Short Form 36 (SF-36). Values ranged from 0 to 100. Higher values mean better outcome. | Change from baseline to 12 weeks | 
| Change in Gut microbiota composition | DNA sequencing to determine gut microbiota composition (e.g., phylum and genera) | Change from baseline to 12 weeks | 
| Change in fecal microbiota diversity | DNA sequencing to determine gut microbiota diversity (e.g., beta and alpha) | Change from baseline to 12 weeks | 
| Change in Cardiorespiratory Fitness | Cardiorespiratory fitness measured by maximum treadmill test | Change from baseline to 12 weeks | 
| Change in Lower muscular strength | Lower body muscular strength measured by chair stand test. | Change from baseline to 12 weeks | 
| Change in Upper muscular strength | Upper body muscular strength measured by hand grip strength test. | Change from baseline to 12 weeks | 
| Change in walking speed. | Walking speed measured by gait speed test. Higher values mean worse performance. | Change from baseline to 12 weeks | 
| Adherence to the time-restricted eating intervention | Adherence will be assessed by eating records through the mobile phone app. | Change from baseline to 12 weeks | 
| Adherence to the exercise intervention | Adherence will be assessed by number of completed exercise sessions. | Change from baseline to 12 weeks | 
| Change in hepatic fat content | Hepatic fat content will be assessed by Magnetic Resonance Imaging (MRI) | Change from 12 weeks of intervention to 12 months |