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

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.

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

- 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

- 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