Back to resultsComplex Effects of Dietary Manipulation on Metabolic Function, Inflammation and Health
Primary Purpose
Obesity, Insulin Resistance
Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Metabolically abnormal obese - Mediterranean diet
Metabolically abnormal obese - Low carbohydrate ketogenic diet
Metabolically abnormal obese - Plant-based, very-low-fat diet
Sponsored by
About this trial
This is an interventional other trial for Obesity
Eligibility Criteria
Inclusion Criteria:
- Metabolically normal lean subjects must have a BMI ≥18.5 and ≤24.9 kg/m2; Obese subjects must have a BMI ≥30.0 and ≤50.0 kg/m2
- Metabolically normal lean and obese subjects must have intrahepatic triglyceride (IHTG) content ≤5%; plasma triglyceride (TG) concentration <150 mg/dl; fasting plasma glucose concentration <100 mg/dl, 2-hr oral glucose tolerance plasma glucose concentration <140 mg/dl, and hemoglobin A1C ≤5.6%
- Metabolically abnormal obese subjects must have intrahepatic triglyceride (IHTG) content ≥5.6%; HbA1C ≥5.7%, or fasting plasma glucose concentration ≥100 mg/dl, or 2-hr oral glucose tolerance test (OGTT) plasma glucose concentration ≥140 mg/dl.
Exclusion Criteria:
- Medical, surgical, or biological menopause
- Previous bariatric surgery where the gastrointestinal tract is reconstructed such as Roux-en-Y, sleeve gastrectomy and biliopancreatic diversion surgeries
- Laparoscopic adjustable gastric band (lab band) surgery within the last 3 years
- Structured exercise ≥250 min per week (e.g., brisk walking)
- Unstable weight (>4% change during the last 2 months before entering the study)
- Significant organ system dysfunction (e.g., diabetes requiring medications, severe pulmonary, kidney or cardiovascular disease)
- Polycystic ovary syndrome
- Cancer or cancer that has been in remission for <5 years
- Major psychiatric illness
- Conditions that render subject unable to complete all testing procedures (e.g., severe ambulatory impairments, limb amputations, or metal implants that interfere with imaging procedures; coagulation disorders)
- Use of medications that are known to affect the study outcome measures (e.g., steroids, non-statin lipid-lowering medications) or increase the risk of study procedures (e.g., anticoagulants) and that cannot be temporarily discontinued for this study
- Use of antibiotics in last 60 days
- Smoke cigarettes > 10 cigarettes/week
- Use marijuana >2 x/week, or use of illegal drugs
- Men who consume >21 units (e.g. glass of wine or bottle of beer) of alcohol per week and women who consume >14 units of alcohol per week
- Pregnant or lactating women
- Vegans, vegetarians, those with lactose intolerance and/or severe aversions/sensitivities to eggs, fish, nuts, wheat and soy, and/or any individuals with food allergies that induce an anaphylactic response
- Persons who are not able to grant voluntary informed consent
- Persons who are unable or unwilling to follow the study protocol or who, for any reason, the research team considers not an appropriate candidate for this study, including non-compliance with screening appointments or study visits
Sites / Locations
- Washington University School of MedicineRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
No Intervention
No Intervention
Experimental
Experimental
Experimental
Arm Label
Metabolically normal lean - Baseline testing only
Metabolically normal obese - Baseline testing only
Metabolically abnormal obese - Mediterranean diet
Metabolically abnormal obese - Low carbohydrate ketogenic diet
Metabolically abnormal obese - Plant-based very-low-fat diet
Arm Description
Metabolically normal lean - Lean individuals that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content. Dietary intervention - None.
Metabolically normal obese - Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content. Dietary intervention - None.
Metabolically abnormal obese - Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver. Dietary intervention - A nutritionally balanced diet that includes fruits, vegetables, fish, beans, whole grains, and olive oil with approximately 50% of daily calories coming from complex carbohydrates, 30% of calories from fat, and 20% of calories from protein.
Metabolically abnormal obese - Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver. Dietary intervention - A very-low-carbohydrate, adequate protein, high-fat diet containing 20 grams of carbohydrate or less per day (about 5% of calories), derived mainly from vegetables.
Metabolically abnormal obese - Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver. Dietary intervention - A plant-based diet high in complex carbohydrates and low in fat, protein, and sodium, with approximately 70% of daily calories from carbohydrates, 15% from fat, and 15% from protein.
Outcomes
Primary Outcome Measures
Insulin sensitivity
Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure
Change in insulin sensitivity
Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure
Secondary Outcome Measures
24-hour glucose concentrations
Glucose concentrations will be evaluated from frequent blood samples over a 24 h period
Change in 24-hour glucose concentrations
Glucose concentrations will be evaluated from frequent blood samples over a 24 h period
24-hour hormone concentrations
Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period
Change in 24-hour hormone concentrations
Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period
24-hour cytokine concentrations
Plasma cytokine concentrations will be evaluated from frequent blood sampling over a 24 h period
β-cell function
β-cell function will be assessed from a modified oral glucose tolerance test
Change in β-cell function
β-cell function will be assessed from a modified oral glucose tolerance test
Insulin clearance
Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure
Insulin clearance
Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure
Fat mass and fat free mass
Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
Change in fat mass and fat free mass
Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
Exosome-mediated intercellular signaling
Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue
Change in exosome-mediated intercellular signaling
Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue
Abdominal adipose tissue volumes
Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Change in abdominal adipose tissue volumes
Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Leg adipose tissue volumes
Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Change in leg adipose tissue volumes
Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Intra-hepatic triglyceride content
Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques
Change in intra-hepatic triglyceride content
Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques
Gut microbiome
Gut microbiota, meta-transcriptome (bacterial RNA sequencing to determine what proteins can be made by the microbiota) and the meta-metabolome (metabolites made by the microbiota) will be assessed
Change in gut microbiome
Gut microbiota, meta-transcriptome (bacterial RNA sequencing to determine what proteins can be made by the microbiota) and the meta-metabolome (metabolites made by the microbiota) will be assessed
Plasma lipid profile
Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques
Change in plasma lipid profile
Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques
Aerobic fitness
Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue
Change in aerobic fitness
Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue
Carotid artery intima media thickness
Carotid artery intima media thickness will be assessed by ultrasound imaging
Change in carotid artery intima media thickness
Carotid artery intima media thickness will be assessed by ultrasound imaging
Cardiac structure and function
Ultrasound techniques will be used to assess cardiac structure and function
Change in cardiac structure and function
Ultrasound techniques will be used to assess cardiac structure and function
Endothelial function
Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.
Change in endothelial function
Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.
Arterial stiffness
Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
Change in arterial stiffness
Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
Physical activity
Physical activity will be assessed using tri-axial accelerometry
Change in physical activity
Physical activity will be assessed using tri-axial accelerometry
Sleep efficiency
Sleep efficiency will be assessed using tri-axial accelerometry
Change in sleep efficiency
Sleep efficiency will be assessed using tri-axial accelerometry
Rate of incorporation of 2H2O into lipids
Metabolic pathways relating to lipid (fat) synthesis in the liver and adipose tissue (fat) will be assessed by heavy water (2H2O) ingestion followed by fat biopsies and blood sampling
Change in the rate of incorporation of 2H2O into lipids
Metabolic pathways relating to lipid (fat) synthesis in the liver and adipose tissue (fat) will be assessed by heavy water (2H2O) ingestion followed by fat biopsies and blood sampling
Rate of incorporation of 2H2O into proteins
Metabolic pathways relating to protein synthesis in the muscle and adipose tissue will be assessed by heavy water (2H2O) ingestion followed by skeletal muscle and and adipose tissue biopsies and blood sampling
Change in the rate of incorporation of 2H2O into proteins
Metabolic pathways relating to protein synthesis in the muscle and adipose tissue will be assessed by heavy water (2H2O) ingestion followed by skeletal muscle and and adipose tissue biopsies and blood sampling
Taste intensity
Subjects will be evaluated by using the NIH toolbox Taste Intensity Test
Change in taste intensity
Subjects will be evaluated by using the NIH toolbox Taste Intensity Test
Sweet taste palatability
Sweet palatability will be assessed using the general Labeled Magnitude Scale
Change in sweet taste palatability
Sweet palatability will be assessed using the general Labeled Magnitude Scale
Immune function
Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques.
Change in immune function
Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques.
Food consumption-induced changes in brain blood flow
Food consumption-induced changes in brain blood flow will be assessed by blood-oxygen dependent (BOLD) and arterial spin labeling using functional magnetic resonance imaging (fMRI) techniques
Change in food consumption-induced changes in brain blood flow
Food consumption-induced changes in brain blood flow will be assessed by blood-oxygen dependent (BOLD) and arterial spin labeling using functional magnetic resonance imaging (fMRI) techniques
Transcriptome in blood, muscle and adipose tissue
The transcriptome (all RNA that are responsible for making proteins from DNA templates) will be evaluated by using RNA sequencing techniques
Change in transcriptome in blood, muscle and adipose tissue
The transcriptome (all RNA that are responsible for making proteins from DNA templates) will be evaluated by using RNA sequencing techniques
Epigenome in blood, muscle and adipose tissue
The epigenome (chemical modifications of DNA that signal genes to be on or off) will be evaluated by using Illumina Infinium HumanMethylation450 BeadChip assays.
Change in epigenome in blood, muscle and adipose tissue
The epigenome (chemical modifications of DNA that signal genes to be on or off) will be evaluated by using Illumina Infinium HumanMethylation450 BeadChip assays.
Dopamine receptor binding potential
Dopamine receptor binding potential will be assessed by Positron Emission Tomography (PET) using [11C]raclopride in the fasted and fed states
Subcutaneous abdominal adipose tissue oxygen tension
Oxygen tension will be assessed in subcutaneous abdominal adipose tissue in the abdomen using oxygen-sensitive fiber-optic probes (OxyLiteTM, Oxford Optronix, Ltd)
Full Information
NCT ID
NCT02706262
First Posted
February 24, 2016
Last Updated
August 4, 2023
Sponsor
Washington University School of Medicine
Collaborators
Pershing Square Foundation
1. Study Identification
Unique Protocol Identification Number
NCT02706262
Brief Title
Complex Effects of Dietary Manipulation on Metabolic Function, Inflammation and Health
Official Title
Complex Effects of Dietary Manipulation on Metabolic Function, Inflammation and Health
Study Type
Interventional
2. Study Status
Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 2016 (undefined)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
Pershing Square Foundation
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this research study is to 1) understand how some, but not all people with obesity develop obesity related conditions such as type 2 diabetes and cardiovascular disease, and 2) compare the effects of 3 popular weight loss diets (Mediterranean, low-carbohydrate, or a very-low-fat plant-based diet) in people with obesity.
Detailed Description
Obesity is associated with a constellation of cardiometabolic abnormalities (including insulin resistance, elevated blood pressure and dyslipidemia) that are risk factors for diabetes and cardiovascular disease. However, not all people experience the typical "complications" associated with obesity. Approximately 25% of obese people are protected from the adverse metabolic effects of excess fat accumulation and are considered metabolically-normal, based on their normal response to insulin. The mechanisms responsible for the development of insulin resistance and cardiometabolic complications in some, but not all, obese persons are unknown.
In people that do develop the typical "complications" associated with obesity weight loss has profound therapeutic effects. Currently, there are three distinctly different types of diets that have demonstrated considerable benefits in improving cardiometabolic health in both lean and obese people: 1) a Mediterranean diet, 2) a low-carbohydrate, ketogenic diet, and 3) a plant-based, very-low-fat diet. However, there is considerable inter-individual variability in body weight loss among people in response to any given diet, and it is not known why some people lose more weight with one diet than another. The mechanisms responsible for the different weight and metabolic responses to specific types of diets and the independent effects of weight loss and dietary macronutrient composition on cardiometabolic health are unclear.
The overarching goal of this project is therefore to fill these gaps in knowledge by conducting a careful cross-sectional characterization of metabolically normal lean, metabolically normal obese and metabolically abnormal obese individuals to compare body composition, body fat distribution, the plasma metabolome, systemic and adipose tissue inflammation and immune system function, adipose tissue and muscle biological function, the gut microbiome, the brain's structure, cognitive function and central reward mechanisms, and taste sensation between groups. . Metabolically abnormal obese participants will then be randomized to follow a Mediterranean, a low-carbohydrate ketogenic or a plant-based, very-low-fat diet to examine the different effects of these diets on the above outcomes with the purpose to determine the beneficial or potentially harmful effects of these different diets.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Obesity, Insulin Resistance
7. Study Design
Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
180 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Metabolically normal lean - Baseline testing only
Arm Type
No Intervention
Arm Description
Metabolically normal lean - Lean individuals that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content.
Dietary intervention - None.
Arm Title
Metabolically normal obese - Baseline testing only
Arm Type
No Intervention
Arm Description
Metabolically normal obese - Persons with obesity that have good glucose (sugar) control, normal plasma triglyceride (fat) levels and a low liver fat content.
Dietary intervention - None.
Arm Title
Metabolically abnormal obese - Mediterranean diet
Arm Type
Experimental
Arm Description
Metabolically abnormal obese - Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver.
Dietary intervention - A nutritionally balanced diet that includes fruits, vegetables, fish, beans, whole grains, and olive oil with approximately 50% of daily calories coming from complex carbohydrates, 30% of calories from fat, and 20% of calories from protein.
Arm Title
Metabolically abnormal obese - Low carbohydrate ketogenic diet
Arm Type
Experimental
Arm Description
Metabolically abnormal obese - Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver.
Dietary intervention - A very-low-carbohydrate, adequate protein, high-fat diet containing 20 grams of carbohydrate or less per day (about 5% of calories), derived mainly from vegetables.
Arm Title
Metabolically abnormal obese - Plant-based very-low-fat diet
Arm Type
Experimental
Arm Description
Metabolically abnormal obese - Persons with obesity with glucose levels higher than recommended and a moderate to high amount of fat in the liver.
Dietary intervention - A plant-based diet high in complex carbohydrates and low in fat, protein, and sodium, with approximately 70% of daily calories from carbohydrates, 15% from fat, and 15% from protein.
Intervention Type
Other
Intervention Name(s)
Metabolically abnormal obese - Mediterranean diet
Intervention Description
The effect of consuming a Mediterranean diet will be examined over 3 different phases: (i) weight maintenance for 4 to 8 weeks, with all meals provided; (ii) controlled 7-10% weight loss with caloric intake reduced by 25% to achieve the desired amount of weight loss in about 4 to 5 months with all meals provided; and (iii) Independent weight loss for about 4 months. During the independent weight loss phase of the study subjects will be asked to continue to consume a Mediterranean diet but will prepare all their food at home. No food will be provided during this portion of the study.
Intervention Type
Other
Intervention Name(s)
Metabolically abnormal obese - Low carbohydrate ketogenic diet
Intervention Description
The effect of consuming a low-carbohydrate, ketogenic diet will be examined over 3 different phases: (i) weight maintenance for 4 to 8 weeks, with all meals provided; (ii) controlled 7-10% weight loss with caloric intake reduced by 25% to achieve the desired amount of weight loss in about 4 to 5 months with all meals provided; and (iii) Independent weight loss for about 4 months. During the independent weight loss phase of the study subjects will be asked to continue to consume a low carbohydrate ketogenic diet but will prepare all their food at home. No food will be provided during this portion of the study.
Intervention Type
Other
Intervention Name(s)
Metabolically abnormal obese - Plant-based, very-low-fat diet
Intervention Description
The effect of consuming a plant-based, very-low-fat diet will be examined over 3 different phases: (i) weight maintenance for 4 to 8 weeks, with all meals provided; (ii) controlled 7-10% weight loss with caloric intake reduced by 25% to achieve the desired amount of weight loss in about 4 to 5 months with all meals provided; and (iii) Independent weight loss for about 4 months. During the independent weight loss phase of the study subjects will be asked to continue to consume a plant-based, very-low-fat diet but will prepare all their food at home. No food will be provided during this portion of the study.
Primary Outcome Measure Information:
Title
Insulin sensitivity
Description
Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in insulin sensitivity
Description
Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure
Time Frame
Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)
Secondary Outcome Measure Information:
Title
24-hour glucose concentrations
Description
Glucose concentrations will be evaluated from frequent blood samples over a 24 h period
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in 24-hour glucose concentrations
Description
Glucose concentrations will be evaluated from frequent blood samples over a 24 h period
Time Frame
Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)
Title
24-hour hormone concentrations
Description
Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in 24-hour hormone concentrations
Description
Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period
Time Frame
Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)
Title
24-hour cytokine concentrations
Description
Plasma cytokine concentrations will be evaluated from frequent blood sampling over a 24 h period
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
β-cell function
Description
β-cell function will be assessed from a modified oral glucose tolerance test
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in β-cell function
Description
β-cell function will be assessed from a modified oral glucose tolerance test
Time Frame
Before and after 7-10% weight loss (~6-7 months) and independent weight loss (12 months) in metabolically abnormal obese individuals only.
Title
Insulin clearance
Description
Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Insulin clearance
Description
Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only.
Title
Fat mass and fat free mass
Description
Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in fat mass and fat free mass
Description
Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
Time Frame
Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months)
Title
Exosome-mediated intercellular signaling
Description
Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in exosome-mediated intercellular signaling
Description
Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue
Time Frame
Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months)
Title
Abdominal adipose tissue volumes
Description
Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in abdominal adipose tissue volumes
Description
Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Time Frame
Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months)
Title
Leg adipose tissue volumes
Description
Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in leg adipose tissue volumes
Description
Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Time Frame
Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months)
Title
Intra-hepatic triglyceride content
Description
Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in intra-hepatic triglyceride content
Description
Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques
Time Frame
Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months)
Title
Gut microbiome
Description
Gut microbiota, meta-transcriptome (bacterial RNA sequencing to determine what proteins can be made by the microbiota) and the meta-metabolome (metabolites made by the microbiota) will be assessed
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in gut microbiome
Description
Gut microbiota, meta-transcriptome (bacterial RNA sequencing to determine what proteins can be made by the microbiota) and the meta-metabolome (metabolites made by the microbiota) will be assessed
Time Frame
Before and during 4 to 8-weeks of weight maintenance, 7-10% weight loss (~6-7 months) and independent weight loss (12 months)
Title
Plasma lipid profile
Description
Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in plasma lipid profile
Description
Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques
Time Frame
Before and after 4 to 8-weeks of weight maintenance, after 7-10% weight loss (~6-7 months) and after independent weight loss (12 months)
Title
Aerobic fitness
Description
Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in aerobic fitness
Description
Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals randomized to the plant-based very-low-fat diet only
Title
Carotid artery intima media thickness
Description
Carotid artery intima media thickness will be assessed by ultrasound imaging
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in carotid artery intima media thickness
Description
Carotid artery intima media thickness will be assessed by ultrasound imaging
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Cardiac structure and function
Description
Ultrasound techniques will be used to assess cardiac structure and function
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in cardiac structure and function
Description
Ultrasound techniques will be used to assess cardiac structure and function
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Endothelial function
Description
Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in endothelial function
Description
Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Arterial stiffness
Description
Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in arterial stiffness
Description
Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Physical activity
Description
Physical activity will be assessed using tri-axial accelerometry
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in physical activity
Description
Physical activity will be assessed using tri-axial accelerometry
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Sleep efficiency
Description
Sleep efficiency will be assessed using tri-axial accelerometry
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in sleep efficiency
Description
Sleep efficiency will be assessed using tri-axial accelerometry
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Rate of incorporation of 2H2O into lipids
Description
Metabolic pathways relating to lipid (fat) synthesis in the liver and adipose tissue (fat) will be assessed by heavy water (2H2O) ingestion followed by fat biopsies and blood sampling
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in the rate of incorporation of 2H2O into lipids
Description
Metabolic pathways relating to lipid (fat) synthesis in the liver and adipose tissue (fat) will be assessed by heavy water (2H2O) ingestion followed by fat biopsies and blood sampling
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Rate of incorporation of 2H2O into proteins
Description
Metabolic pathways relating to protein synthesis in the muscle and adipose tissue will be assessed by heavy water (2H2O) ingestion followed by skeletal muscle and and adipose tissue biopsies and blood sampling
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in the rate of incorporation of 2H2O into proteins
Description
Metabolic pathways relating to protein synthesis in the muscle and adipose tissue will be assessed by heavy water (2H2O) ingestion followed by skeletal muscle and and adipose tissue biopsies and blood sampling
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Taste intensity
Description
Subjects will be evaluated by using the NIH toolbox Taste Intensity Test
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in taste intensity
Description
Subjects will be evaluated by using the NIH toolbox Taste Intensity Test
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Sweet taste palatability
Description
Sweet palatability will be assessed using the general Labeled Magnitude Scale
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in sweet taste palatability
Description
Sweet palatability will be assessed using the general Labeled Magnitude Scale
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Immune function
Description
Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques.
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in immune function
Description
Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques.
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Food consumption-induced changes in brain blood flow
Description
Food consumption-induced changes in brain blood flow will be assessed by blood-oxygen dependent (BOLD) and arterial spin labeling using functional magnetic resonance imaging (fMRI) techniques
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in food consumption-induced changes in brain blood flow
Description
Food consumption-induced changes in brain blood flow will be assessed by blood-oxygen dependent (BOLD) and arterial spin labeling using functional magnetic resonance imaging (fMRI) techniques
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Transcriptome in blood, muscle and adipose tissue
Description
The transcriptome (all RNA that are responsible for making proteins from DNA templates) will be evaluated by using RNA sequencing techniques
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in transcriptome in blood, muscle and adipose tissue
Description
The transcriptome (all RNA that are responsible for making proteins from DNA templates) will be evaluated by using RNA sequencing techniques
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Epigenome in blood, muscle and adipose tissue
Description
The epigenome (chemical modifications of DNA that signal genes to be on or off) will be evaluated by using Illumina Infinium HumanMethylation450 BeadChip assays.
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Title
Change in epigenome in blood, muscle and adipose tissue
Description
The epigenome (chemical modifications of DNA that signal genes to be on or off) will be evaluated by using Illumina Infinium HumanMethylation450 BeadChip assays.
Time Frame
Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Title
Dopamine receptor binding potential
Description
Dopamine receptor binding potential will be assessed by Positron Emission Tomography (PET) using [11C]raclopride in the fasted and fed states
Time Frame
Baseline in fasted and fed states in metabolically abnormal obese participants only.
Title
Subcutaneous abdominal adipose tissue oxygen tension
Description
Oxygen tension will be assessed in subcutaneous abdominal adipose tissue in the abdomen using oxygen-sensitive fiber-optic probes (OxyLiteTM, Oxford Optronix, Ltd)
Time Frame
Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Metabolically normal lean subjects must have a BMI ≥18.5 and ≤24.9 kg/m2; Obese subjects must have a BMI ≥30.0 and ≤50.0 kg/m2
Metabolically normal lean and obese subjects must have intrahepatic triglyceride (IHTG) content ≤5%; plasma triglyceride (TG) concentration <150 mg/dl; fasting plasma glucose concentration <100 mg/dl, 2-hr oral glucose tolerance plasma glucose concentration <140 mg/dl, and hemoglobin A1C ≤5.6%
Metabolically abnormal obese subjects must have intrahepatic triglyceride (IHTG) content ≥5.6%; HbA1C ≥5.7%, or fasting plasma glucose concentration ≥100 mg/dl, or 2-hr oral glucose tolerance test (OGTT) plasma glucose concentration ≥140 mg/dl.
Exclusion Criteria:
Medical, surgical, or biological menopause
Previous bariatric surgery where the gastrointestinal tract is reconstructed such as Roux-en-Y, sleeve gastrectomy and biliopancreatic diversion surgeries
Laparoscopic adjustable gastric band (lab band) surgery within the last 3 years
Structured exercise ≥250 min per week (e.g., brisk walking)
Unstable weight (>4% change during the last 2 months before entering the study)
Significant organ system dysfunction (e.g., diabetes requiring medications, severe pulmonary, kidney or cardiovascular disease)
Polycystic ovary syndrome
Cancer or cancer that has been in remission for <5 years
Major psychiatric illness
Conditions that render subject unable to complete all testing procedures (e.g., severe ambulatory impairments, limb amputations, or metal implants that interfere with imaging procedures; coagulation disorders)
Use of medications that are known to affect the study outcome measures (e.g., steroids, non-statin lipid-lowering medications) or increase the risk of study procedures (e.g., anticoagulants) and that cannot be temporarily discontinued for this study
Use of antibiotics in last 60 days
Smoke cigarettes > 10 cigarettes/week
Use marijuana >2 x/week, or use of illegal drugs
Men who consume >21 units (e.g. glass of wine or bottle of beer) of alcohol per week and women who consume >14 units of alcohol per week
Pregnant or lactating women
Vegans, vegetarians, those with lactose intolerance and/or severe aversions/sensitivities to eggs, fish, nuts, wheat and soy, and/or any individuals with food allergies that induce an anaphylactic response
Persons who are not able to grant voluntary informed consent
Persons who are unable or unwilling to follow the study protocol or who, for any reason, the research team considers not an appropriate candidate for this study, including non-compliance with screening appointments or study visits
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Johanna Sonnenschein
Phone
314-273-1879
Email
nutritionresearch@wustl.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Samuel Klein, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Johanna Sonnenschein
Phone
314-273-1879
Email
nutritionresearch@wustl.edu
First Name & Middle Initial & Last Name & Degree
Samuel Klein, MD
12. IPD Sharing Statement
Citations:
PubMed Identifier
31528845
Citation
Seo JB, Riopel M, Cabrales P, Huh JY, Bandyopadhyay GK, Andreyev AY, Murphy AN, Beeman SC, Smith GI, Klein S, Lee YS, Olefsky JM. Knockdown of Ant2 Reduces Adipocyte Hypoxia And Improves Insulin Resistance in Obesity. Nat Metab. 2019 Jan;1(1):86-97. doi: 10.1038/s42255-018-0003-x. Epub 2018 Nov 19.
Results Reference
result
PubMed Identifier
31454790
Citation
Stern JH, Smith GI, Chen S, Unger RH, Klein S, Scherer PE. Obesity dysregulates fasting-induced changes in glucagon secretion. J Endocrinol. 2019 Nov;243(2):149-160. doi: 10.1530/JOE-19-0201.
Results Reference
result
PubMed Identifier
32086877
Citation
Eisenstein SA, Black KJ, Samara A, Koller JM, Dunn JP, Hershey T, Klein S, Smith GI. Striatal Dopamine Responses to Feeding are Altered in People with Obesity. Obesity (Silver Spring). 2020 Apr;28(4):765-771. doi: 10.1002/oby.22753. Epub 2020 Feb 21.
Results Reference
result
PubMed Identifier
32099031
Citation
Ding X, Iyer R, Novotny C, Metzger D, Zhou HH, Smith GI, Yoshino M, Yoshino J, Klein S, Swaminath G, Talukdar S, Zhou Y. Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction. Sci Rep. 2020 Feb 25;10(1):3417. doi: 10.1038/s41598-020-60290-1.
Results Reference
result
PubMed Identifier
32191646
Citation
Smith GI, Polidori DC, Yoshino M, Kearney ML, Patterson BW, Mittendorfer B, Klein S. Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics. J Clin Invest. 2020 Jun 1;130(6):3305-3314. doi: 10.1172/JCI136756.
Results Reference
result
PubMed Identifier
31805015
Citation
Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, Okunade AL, Patterson BW, Nyangau E, Field T, Sirlin CB, Talukdar S, Hellerstein MK, Klein S. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest. 2020 Mar 2;130(3):1453-1460. doi: 10.1172/JCI134165.
Results Reference
result
PubMed Identifier
33164985
Citation
Cifarelli V, Beeman SC, Smith GI, Yoshino J, Morozov D, Beals JW, Kayser BD, Watrous JD, Jain M, Patterson BW, Klein S. Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity. J Clin Invest. 2020 Dec 1;130(12):6688-6699. doi: 10.1172/JCI141828.
Results Reference
result
PubMed Identifier
33743554
Citation
Beals JW, Smith GI, Shankaran M, Fuchs A, Schweitzer GG, Yoshino J, Field T, Matthews M, Nyangau E, Morozov D, Mittendorfer B, Hellerstein MK, Klein S. Increased Adipose Tissue Fibrogenesis, Not Impaired Expandability, Is Associated With Nonalcoholic Fatty Liver Disease. Hepatology. 2021 Sep;74(3):1287-1299. doi: 10.1002/hep.31822. Epub 2021 Jun 22.
Results Reference
result
PubMed Identifier
34004161
Citation
Fuchs A, Samovski D, Smith GI, Cifarelli V, Farabi SS, Yoshino J, Pietka T, Chang SW, Ghosh S, Myckatyn TM, Klein S. Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty Liver Disease. Gastroenterology. 2021 Sep;161(3):968-981.e12. doi: 10.1053/j.gastro.2021.05.008. Epub 2021 May 15.
Results Reference
result
PubMed Identifier
35817849
Citation
Farabi SS, Smith GI, Schweitzer GG, Stein RI, Klein S. Do lifestyle factors and quality of life differ in people with metabolically healthy and unhealthy obesity? Int J Obes (Lond). 2022 Oct;46(10):1778-1785. doi: 10.1038/s41366-022-01180-6. Epub 2022 Jul 11.
Results Reference
result
PubMed Identifier
34905513
Citation
Mittendorfer B, Patterson BW, Smith GI, Yoshino M, Klein S. beta Cell function and plasma insulin clearance in people with obesity and different glycemic status. J Clin Invest. 2022 Feb 1;132(3):e154068. doi: 10.1172/JCI154068.
Results Reference
result
PubMed Identifier
37475685
Citation
Dunn JP, Lamichhane B, Smith GI, Garner A, Wallendorf M, Hershey T, Klein S. Dorsal striatal response to taste is modified by obesity and insulin resistance. Obesity (Silver Spring). 2023 Aug;31(8):2065-2075. doi: 10.1002/oby.23799.
Results Reference
result
PubMed Identifier
37365374
Citation
Beals JW, Kayser BD, Smith GI, Schweitzer GG, Kirbach K, Kearney ML, Yoshino J, Rahman G, Knight R, Patterson BW, Klein S. Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes. Nat Metab. 2023 Jul;5(7):1221-1235. doi: 10.1038/s42255-023-00829-4. Epub 2023 Jun 26.
Results Reference
result
Learn more about this trial
Complex Effects of Dietary Manipulation on Metabolic Function, Inflammation and Health
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