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NCT Number: NCT02706262

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

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.

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Key information

Conditions

Obesity Body Weight Glucose Metabolism Disorders Hyperinsulinism Insulin Resistance Metabolic Diseases Nutrition Disorders Nutritional and Metabolic Diseases Overnutrition Overweight Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

18 year–55 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Metabolically abnormal obese - Mediterranean diet

Other

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 diet

Other

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.

Metabolically abnormal obese - Plant-based, very-low-fat diet

Other

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 Visits

Behavioral

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

Primary outcomes

  1. Insulin sensitivity

    Time frame: 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

  2. Change in insulin sensitivity

    Time frame: 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 outcomes

  1. 24-hour glucose concentrations

    Time frame: 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

  2. Change in 24-hour glucose concentrations

    Time frame: 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

  3. 24-hour hormone concentrations

    Time frame: 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

  4. Change in 24-hour hormone concentrations

    Time frame: 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

  5. 24-hour cytokine concentrations

    Time frame: 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

  6. β-cell function

    Time frame: 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

  7. Change in β-cell function

    Time frame: 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

  8. Insulin clearance

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

    Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure

  9. Insulin clearance

    Time frame: 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

  10. Fat mass and fat free mass

    Time frame: 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)

  11. Change in fat mass and fat free mass

    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)

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

  12. Exosome-mediated intercellular signaling

    Time frame: 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

  13. Change in exosome-mediated intercellular signaling

    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)

    Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue

  14. Abdominal adipose tissue volumes

    Time frame: 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)

  15. Change in abdominal adipose tissue volumes

    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 subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)

  16. Leg adipose tissue volumes

    Time frame: 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)

  17. Change in leg adipose tissue volumes

    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)

    Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)

  18. Intra-hepatic triglyceride content

    Time frame: 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

  19. Change in intra-hepatic triglyceride content

    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 will be assessed by magnetic resonance techniques

  20. Gut microbiome

    Time frame: 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

  21. Change in gut microbiome

    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)

    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

  22. Plasma lipid profile

    Time frame: 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

  23. Change in plasma lipid profile

    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)

    Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques

  24. Aerobic fitness

    Time frame: 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

  25. Change in aerobic fitness

    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

    Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue

  26. Carotid artery intima media thickness

    Time frame: 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

  27. Change in carotid artery intima media thickness

    Time frame: 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

  28. Cardiac structure and function

    Time frame: 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

  29. Change in cardiac structure and function

    Time frame: 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

  30. Endothelial function

    Time frame: 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.

  31. Change in endothelial function

    Time frame: 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.

  32. Arterial stiffness

    Time frame: 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)

  33. Change in arterial stiffness

    Time frame: 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)

  34. Physical activity

    Time frame: 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

  35. Change in physical activity

    Time frame: 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

  36. Sleep efficiency

    Time frame: 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

  37. Change in sleep efficiency

    Time frame: 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

  38. Rate of incorporation of 2H2O into lipids

    Time frame: 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

  39. Change in the rate of incorporation of 2H2O into lipids

    Time frame: 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

  40. Rate of incorporation of 2H2O into proteins

    Time frame: 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

  41. 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

    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

  42. Taste intensity

    Time frame: 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

  43. Change in taste intensity

    Time frame: 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

  44. Sweet taste palatability

    Time frame: 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

  45. Change in sweet taste palatability

    Time frame: 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

  46. Immune function

    Time frame: 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.

  47. Change in immune function

    Time frame: 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.

  48. Food consumption-induced changes in brain blood flow

    Time frame: 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

  49. Change in food consumption-induced changes in brain blood flow

    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 will be assessed by blood-oxygen dependent (BOLD) and arterial spin labeling using functional magnetic resonance imaging (fMRI) techniques

  50. Transcriptome in blood, muscle and adipose tissue

    Time frame: 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

  51. Change in transcriptome in blood, muscle and adipose tissue

    Time frame: 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

  52. Epigenome in blood, muscle and adipose tissue

    Time frame: 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.

  53. Change in epigenome in blood, muscle and adipose tissue

    Time frame: 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.

  54. Dopamine receptor binding potential

    Time frame: 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

  55. Subcutaneous abdominal adipose tissue oxygen tension

    Time frame: 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)

  56. Change in β-cell function

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

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

  57. Insulin clearance

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

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

  58. Change in fat mass and fat free mass

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

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

  59. Change in intra-hepatic triglyceride content

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

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

Sponsors and collaborators

Lead sponsor

Washington University School of Medicine

Other

Registry information

Important dates

Study start
2016
Primary completion
2025
Study completion
2027
First posted
Mar 11, 2016
Registry last updated
Jan 27, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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