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

N/AActive Not RecruitingNCT02706262

Washington University School of Medicine180 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

NONE

Enrollment

180

Conditions

Obesity Insulin Resistance

Interventions

Metabolically abnormal obese - Mediterranean dietOTHER

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.

Metabolically abnormal obese - Low carbohydrate ketogenic dietOTHER

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Washington University School of Medicine

St Louis, Missouri, United States

Outcomes

Primary Outcomes

Insulin sensitivity

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).

Change in insulin sensitivity

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 Outcomes

24-hour glucose concentrations

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).

Change in 24-hour glucose concentrations

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)

24-hour hormone concentrations

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).

Change in 24-hour hormone concentrations

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)

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

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.

Annual Follow-up VisitsBEHAVIORAL

Metabolic health will be assessed 1 and 2-years after competing the diet intervention study. No intervention will be performed during the time.

24-hour cytokine concentrations

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).

β-cell function

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).

Change in β-cell function

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.

Insulin clearance

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).

Insulin clearance

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.

Fat mass and fat free mass

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).

Change in fat mass and fat free mass

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)

Exosome-mediated intercellular signaling

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).

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

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)

Abdominal adipose tissue volumes

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).

Change in abdominal adipose tissue volumes

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)

Leg adipose tissue volumes

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).

Change in leg adipose tissue volumes

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)

Intra-hepatic triglyceride content

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).

Change in intra-hepatic triglyceride content

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)

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

Time frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

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

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)

Plasma lipid profile

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).

Change in plasma lipid profile

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)

Aerobic fitness

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).

Change in aerobic fitness

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

Carotid artery intima media thickness

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).

Change in carotid artery intima media thickness

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

Cardiac structure and function

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).

Change in cardiac structure and function

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

Endothelial function

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).

Change in endothelial function

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

Arterial stiffness

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).

Change in arterial stiffness

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

Physical activity

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).

Change in physical activity

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

Sleep efficiency

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).

Change in sleep efficiency

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

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

Time frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

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

Time frame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only

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

Time frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

Change in the rate of incorporation of 2H2O into proteins

Time frame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only

Taste intensity

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).

Change in taste intensity

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

Sweet taste palatability

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).

Change in sweet taste palatability

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

Immune function

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).

Change in immune function

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

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

Time frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

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

Time frame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only

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

Time frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

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

Time frame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only

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.

Time frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

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.

Time frame: Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only

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

Time frame: Baseline in fasted and fed states in metabolically abnormal obese participants only.

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)

Time frame: Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).

Change in β-cell function

β-cell function will be assessed from a modified oral glucose tolerance test

Time frame: Before and at annual follow-up visits (assessed up to 2 years) in metabolically abnormal obese individuals only.

Insulin clearance

Insulin clearance will be assessed from a modified oral glucose tolerance test

Time frame: Before and at annual follow-up visits (assessed up to 2 years) in metabolically abnormal obese individuals only.

Change in fat mass and fat free mass

Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)

Time frame: Before and at annual follow-up visits (assessed up to 2 years) in metabolically abnormal obese individuals only.

Change in intra-hepatic triglyceride content

Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques

Time frame: Before and at annual follow-up visits (assessed up to 2 years) in metabolically abnormal obese individuals only.