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

Obesity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02706262
• Other study ID #: PSQ-201512086
• Status: Recruiting
• Phase: N/A
• Start date: February 2016
• Est. completion date: December 2025

Study information

• Verified date: May 2024
• Source: Washington University School of Medicine
• Contact: Brittney Mason
• Phone: 314-273-1879
• Email: nutritionresearch[@]wustl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 180
• Est. completion date: December 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Inflammation
• Insulin Resistance
• Obesity

Intervention

Other:
• Metabolically abnormal obese - Mediterranean diet
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
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
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.

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (15)

Beals JW, Kayser BD, Smith GI, Schweitzer GG, Kirbach K, Kearney ML, Yoshino J, Rahman G, Knight R, Patterson BW, Klein S. Dietary weight loss-induced improvements in metabolic function are enhanced by exercise in people with obesity and prediabetes. Nat — View Citation

Beals JW, Smith GI, Shankaran M, Fuchs A, Schweitzer GG, Yoshino J, Field T, Matthews M, Nyangau E, Morozov D, Mittendorfer B, Hellerstein MK, Klein S. Increased Adipose Tissue Fibrogenesis, Not Impaired Expandability, Is Associated With Nonalcoholic Fatt — View Citation

Cifarelli V, Beeman SC, Smith GI, Yoshino J, Morozov D, Beals JW, Kayser BD, Watrous JD, Jain M, Patterson BW, Klein S. Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity. J Clin Invest. 2020 Dec 1;130(12): — View Citation

Ding X, Iyer R, Novotny C, Metzger D, Zhou HH, Smith GI, Yoshino M, Yoshino J, Klein S, Swaminath G, Talukdar S, Zhou Y. Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction. Sci — View Citation

Dunn JP, Lamichhane B, Smith GI, Garner A, Wallendorf M, Hershey T, Klein S. Dorsal striatal response to taste is modified by obesity and insulin resistance. Obesity (Silver Spring). 2023 Aug;31(8):2065-2075. doi: 10.1002/oby.23799. — View Citation

Eisenstein SA, Black KJ, Samara A, Koller JM, Dunn JP, Hershey T, Klein S, Smith GI. Striatal Dopamine Responses to Feeding are Altered in People with Obesity. Obesity (Silver Spring). 2020 Apr;28(4):765-771. doi: 10.1002/oby.22753. Epub 2020 Feb 21. — View Citation

Farabi SS, Smith GI, Schweitzer GG, Stein RI, Klein S. Do lifestyle factors and quality of life differ in people with metabolically healthy and unhealthy obesity? Int J Obes (Lond). 2022 Oct;46(10):1778-1785. doi: 10.1038/s41366-022-01180-6. Epub 2022 Jul — View Citation

Fuchs A, Samovski D, Smith GI, Cifarelli V, Farabi SS, Yoshino J, Pietka T, Chang SW, Ghosh S, Myckatyn TM, Klein S. Associations Among Adipose Tissue Immunology, Inflammation, Exosomes and Insulin Sensitivity in People With Obesity and Nonalcoholic Fatty — View Citation

Mittendorfer B, Patterson BW, Smith GI, Yoshino M, Klein S. beta Cell function and plasma insulin clearance in people with obesity and different glycemic status. J Clin Invest. 2022 Feb 1;132(3):e154068. doi: 10.1172/JCI154068. — View Citation

Mittendorfer B, van Vliet S, Smith GI, Petersen MC, Patterson BW, Klein S. Impaired plasma glucose clearance is a key determinant of fasting hyperglycemia in people with obesity. Obesity (Silver Spring). 2024 Mar;32(3):540-546. doi: 10.1002/oby.23963. Epub 2024 Jan 16. — View Citation

Petersen MC, Smith GI, Palacios HH, Farabi SS, Yoshino M, Yoshino J, Cho K, Davila-Roman VG, Shankaran M, Barve RA, Yu J, Stern JH, Patterson BW, Hellerstein MK, Shulman GI, Patti GJ, Klein S. Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity. Cell Metab. 2024 Apr 2;36(4):745-761.e5. doi: 10.1016/j.cmet.2024.03.002. — View Citation

Seo JB, Riopel M, Cabrales P, Huh JY, Bandyopadhyay GK, Andreyev AY, Murphy AN, Beeman SC, Smith GI, Klein S, Lee YS, Olefsky JM. Knockdown of Ant2 Reduces Adipocyte Hypoxia And Improves Insulin Resistance in Obesity. Nat Metab. 2019 Jan;1(1):86-97. doi: — View Citation

Smith GI, Polidori DC, Yoshino M, Kearney ML, Patterson BW, Mittendorfer B, Klein S. Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics. J Clin Invest. 2020 Jun 1;130(6):3305-3314. doi: 10.1172/JCI136756. — View Citation

Smith GI, Shankaran M, Yoshino M, Schweitzer GG, Chondronikola M, Beals JW, Okunade AL, Patterson BW, Nyangau E, Field T, Sirlin CB, Talukdar S, Hellerstein MK, Klein S. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver dis — View Citation

Stern JH, Smith GI, Chen S, Unger RH, Klein S, Scherer PE. Obesity dysregulates fasting-induced changes in glucagon secretion. J Endocrinol. 2019 Nov;243(2):149-160. doi: 10.1530/JOE-19-0201. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Insulin sensitivity	Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Primary	Change in insulin sensitivity	Whole-body insulin sensitivity will be assessed by using the hyperinsulinemic-euglycemic clamp procedure	Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)
Secondary	24-hour glucose concentrations	Glucose concentrations will be evaluated from frequent blood samples over a 24 h period	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in 24-hour glucose concentrations	Glucose concentrations will be evaluated from frequent blood samples over a 24 h period	Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)
Secondary	24-hour hormone concentrations	Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in 24-hour hormone concentrations	Plasma hormone concentrations will be evaluated from frequent blood sampling over a 24 h period	Before and after 4 to 8-weeks of weight maintenance and after 7-10% weight loss (~6-7 months)
Secondary	24-hour cytokine concentrations	Plasma cytokine concentrations will be evaluated from frequent blood sampling over a 24 h period	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	ß-cell function	ß-cell function will be assessed from a modified oral glucose tolerance test	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in ß-cell function	ß-cell function will be assessed from a modified oral glucose tolerance test	Before and after 7-10% weight loss (~6-7 months) and independent weight loss (12 months) in metabolically abnormal obese individuals only.
Secondary	Insulin clearance	Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Insulin clearance	Insulin clearance will be assessed from a modified oral glucose tolerance test and hyperinsulinemic-euglycemic clamp procedure	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only.
Secondary	Fat mass and fat free mass	Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in fat mass and fat free mass	Fat mass and fat free mass will be assessed using dual-energy x-ray absorptiometry (DXA)	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)
Secondary	Exosome-mediated intercellular signaling	Signaling between cells and organs will be examined by isolating exosomes (small extracellular vesicles) from blood and adipose tissue	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	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	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)
Secondary	Abdominal adipose tissue volumes	Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in abdominal adipose tissue volumes	Abdominal subcutaneous and intra-abdominal adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)	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)
Secondary	Leg adipose tissue volumes	Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in leg adipose tissue volumes	Thigh and calf adipose tissue volumes will be assessed by magnetic resonance imagining (MRI)	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)
Secondary	Intra-hepatic triglyceride content	Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in intra-hepatic triglyceride content	Intra-hepatic triglyceride content will be assessed by magnetic resonance techniques	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)
Secondary	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	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	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	Before and during 4 to 8-weeks of weight maintenance, 7-10% weight loss (~6-7 months) and independent weight loss (12 months)
Secondary	Plasma lipid profile	Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in plasma lipid profile	Fasting plasma lipid profile will be assessed by nuclear magnetic resonance (NMR) techniques	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)
Secondary	Aerobic fitness	Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in aerobic fitness	Maximal oxygen consumption will be assessed using indirect calorimetry during a graded exercise test to volitional fatigue	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
Secondary	Carotid artery intima media thickness	Carotid artery intima media thickness will be assessed by ultrasound imaging	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in carotid artery intima media thickness	Carotid artery intima media thickness will be assessed by ultrasound imaging	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	Cardiac structure and function	Ultrasound techniques will be used to assess cardiac structure and function	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in cardiac structure and function	Ultrasound techniques will be used to assess cardiac structure and function	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	Endothelial function	Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in endothelial function	Endothelial function will be assessed using a non-invasive device (EndoPat 2000) in response to reactive hyperemia.	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	Arterial stiffness	Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in arterial stiffness	Arterial stiffness will be assessed using a non-invasive device (SphygmoCor)	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	Physical activity	Physical activity will be assessed using tri-axial accelerometry	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in physical activity	Physical activity will be assessed using tri-axial accelerometry	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	Sleep efficiency	Sleep efficiency will be assessed using tri-axial accelerometry	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in sleep efficiency	Sleep efficiency will be assessed using tri-axial accelerometry	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	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	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	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	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	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	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in the rate of incorporation of 2H2O into proteins	Metabolic pathways relating to protein synthesis in the muscle and adipose tissue will be assessed by heavy water (2H2O) ingestion followed by skeletal muscle and and adipose tissue biopsies and blood sampling	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	Taste intensity	Subjects will be evaluated by using the NIH toolbox Taste Intensity Test	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in taste intensity	Subjects will be evaluated by using the NIH toolbox Taste Intensity Test	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	Sweet taste palatability	Sweet palatability will be assessed using the general Labeled Magnitude Scale	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in sweet taste palatability	Sweet palatability will be assessed using the general Labeled Magnitude Scale	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	Immune function	Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques.	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	Change in immune function	Immune cell populations within plasma and adipose tissue will be profiled using multi-color fluorescence activated cell sorting (FACS) techniques.	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	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	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	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	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	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	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	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	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	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.	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).
Secondary	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.	Before and after 7-10% weight loss (~6-7 months) in metabolically abnormal obese individuals only
Secondary	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	Baseline in fasted and fed states in metabolically abnormal obese participants only.
Secondary	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)	Baseline only (cross-sectional comparison of metabolically normal lean, metabolically normal obese and metabolically abnormal obese subjects).