Complex Effects of Dietary Manipulation on Metabolic Function, Inflammation and Health
Overview
- Phase
- N/A
- Intervention
- Metabolically normal lean - Baseline testing only
- Conditions
- Obesity
- Sponsor
- Washington University School of Medicine
- Enrollment
- 180
- Locations
- 1
- Primary Endpoint
- Insulin sensitivity
- Status
- Active, Not Recruiting
- Last Updated
- 3 months ago
Overview
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.
Investigators
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)
Arms & Interventions
Metabolically normal lean - Baseline testing only
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 - Baseline testing only
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 - 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.
Intervention: 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.
Intervention: Annual Follow-up Visits
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.
Intervention: 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.
Intervention: Annual Follow-up Visits
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.
Intervention: 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.
Intervention: Annual Follow-up Visits
Outcomes
Primary Outcomes
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
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
- 24-hour glucose concentrations(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- 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))
- 24-hour hormone concentrations(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- 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))
- 24-hour cytokine concentrations(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- β-cell function(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in β-cell function(Before and at annual follow-up visits (assessed up to 2 years) in metabolically abnormal obese individuals only.)
- Insulin clearance(Before and at annual follow-up visits (assessed up to 2 years) in metabolically abnormal obese individuals only.)
- Fat mass and fat free mass(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(Before and at annual follow-up visits (assessed up to 2 years) in metabolically abnormal obese individuals only.)
- Exosome-mediated intercellular signaling(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- 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))
- Abdominal adipose tissue volumes(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- 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))
- Leg adipose tissue volumes(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- 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))
- Intra-hepatic triglyceride content(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in intra-hepatic triglyceride content(Before and at annual follow-up visits (assessed up to 2 years) in metabolically abnormal obese individuals only.)
- Gut microbiome(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- 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))
- Plasma lipid profile(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- 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))
- Aerobic fitness(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- 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)
- Carotid artery intima media thickness(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in carotid artery intima media thickness(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Cardiac structure and function(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in cardiac structure and function(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Endothelial function(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in endothelial function(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Arterial stiffness(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in arterial stiffness(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Physical activity(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in physical activity(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Sleep efficiency(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in sleep efficiency(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Rate of incorporation of 2H2O into lipids(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(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Rate of incorporation of 2H2O into proteins(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(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Taste intensity(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in taste intensity(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Sweet taste palatability(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in sweet taste palatability(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Immune function(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Change in immune function(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- 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).)
- 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)
- Transcriptome in blood, muscle and adipose tissue(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(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Epigenome in blood, muscle and adipose tissue(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(Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only)
- Dopamine receptor binding potential(Baseline in fasted and fed states in metabolically abnormal obese participants only.)
- Subcutaneous abdominal adipose tissue oxygen tension(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)
- Insulin clearance(Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).)