Complex Effects of Dietary Manipulation on Metabolic Function, Inflammation and Health

Not Applicable

Recruiting

• Conditions: Obesity; Insulin Resistance
• Interventions: Other: Metabolically abnormal obese - Mediterranean diet; Other: Metabolically abnormal obese - Low carbohydrate ketogenic diet; Other: Metabolically abnormal obese - Plant-based, very-low-fat diet

• Registration Number: NCT02706262
• Lead Sponsor: Washington University School of Medicine

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.

Study Timeline

• Study Start: 2016-02
• Study First Submitted: 2016-02-24
• Study First Submitted QC: 2016-03-07
• Study First Posted: 2016-03-11
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-22
• Last Update Posted: 2024-05-24
• Primary Completion: 2025-07
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 180

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Metabolically abnormal obese - Mediterranean diet	Metabolically abnormal obese - Mediterranean diet	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 - Low carbohydrate ketogenic diet	Metabolically abnormal obese - Low carbohydrate ketogenic diet	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 - Plant-based very-low-fat diet	Metabolically abnormal obese - Plant-based, very-low-fat diet	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.

Primary Outcome Measures

Name	Time	Method
Insulin sensitivity	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure
Change in insulin sensitivity	Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)	Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure

Secondary Outcome Measures

Name	Time	Method
Change in gut microbiome	Before and during 4 to 8-weeks of weight maintenance, 7-10% weight loss (~6-7 months) and independent weight loss (12 months)	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 plasma lipid profile	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)	Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques
Change in carotid artery intima media thickness	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	Carotid artery intima media thickness will be assessed by ultrasound imaging
Cardiac structure and function	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Ultrasound techniques will be used to assess cardiac structure and function
24-hour glucose concentrations	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Glucose concentrations will be evaluated from frequent blood samples over a 24 h period
24-hour hormone concentrations	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period
Change in 24-hour hormone concentrations	Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)	Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period
Fat mass and fat free mass	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
Change in abdominal adipose tissue volumes	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)	Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Change in β-cell function	Before and after 7-10% weight loss (~6-7 months) and independent weight loss (12 months) in metabolically abnormal obese individuals only.	β-cell function will be assessed from a modified oral glucose tolerance test
Insulin clearance	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only.	Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure
β-cell function	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	β-cell function will be assessed from a modified oral glucose tolerance test
Abdominal adipose tissue volumes	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Plasma lipid profile	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques
Leg adipose tissue volumes	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Change in leg adipose tissue volumes	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)	Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)
Aerobic fitness	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue
Change in 24-hour glucose concentrations	Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)	Glucose concentrations will be evaluated from frequent blood samples over a 24 h period
24-hour cytokine concentrations	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Plasma cytokine concentrations will be evaluated from frequent blood sampling over a 24 h period
Change in fat mass and fat free mass	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)	Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)
Exosome-mediated intercellular signaling	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	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	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)	Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue
Intra-hepatic triglyceride content	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques
Change in aerobic fitness	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	Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue
Change in intra-hepatic triglyceride content	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)	Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques
Gut microbiome	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	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
Endothelial function	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.
Change in endothelial function	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.
Carotid artery intima media thickness	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Carotid artery intima media thickness will be assessed by ultrasound imaging
Change in cardiac structure and function	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	Ultrasound techniques will be used to assess cardiac structure and function
Physical activity	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Physical activity will be assessed using tri-axial accelerometry
Arterial stiffness	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
Change in sleep efficiency	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	Sleep efficiency will be assessed using tri-axial accelerometry
Rate of incorporation of 2H2O into lipids	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	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 arterial stiffness	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)
Change in physical activity	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	Physical activity will be assessed using tri-axial accelerometry
Sleep efficiency	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Sleep efficiency will be assessed using tri-axial accelerometry
Change in sweet taste palatability	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	Sweet palatability will be assessed using the general Labeled Magnitude Scale
Change in food consumption-induced changes in brain blood flow	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	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 the rate of incorporation of 2H2O into lipids	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	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	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	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	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	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	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Subjects will be evaluated by using the NIH toolbox Taste Intensity Test
Sweet taste palatability	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Sweet palatability will be assessed using the general Labeled Magnitude Scale
Change in taste intensity	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	Subjects will be evaluated by using the NIH toolbox Taste Intensity Test
Immune function	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques.
Change in immune function	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques.
Transcriptome in blood, muscle and adipose tissue	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	The transcriptome (all RNA that are responsible for making proteins from DNA templates) will be evaluated by using RNA sequencing techniques
Subcutaneous abdominal adipose tissue oxygen tension	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	Oxygen tension will be assessed in subcutaneous abdominal adipose tissue in the abdomen using oxygen-sensitive fiber-optic probes (OxyLiteTM, Oxford Optronix, Ltd)
Food consumption-induced changes in brain blood flow	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	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 transcriptome in blood, muscle and adipose tissue	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	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	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).	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	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only	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	Baseline in fasted and fed states in metabolically abnormal obese participants only.	Dopamine receptor binding potential will be assessed by Positron Emission Tomography (PET) using \[11C\]raclopride in the fasted and fed states

Trial Locations

Locations (1)

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States