This study will test the hypothesis that within a defined range of fructose intake, the ability to convert fructose to glucose (via gluconeogenesis) in the small intestine plays a protective role for the liver, shielding it from the deleterious effects of fructose. We will investigate whether this protective effect of the intestine is impaired in individuals with obesity.

Qualified participants will undergo a sugar tolerance test at baseline and then randomized to undergo four separate outpatient tracer/feeding studies in a crossover fashion. After an overnight fast, a six-hour fed tracer study will be initiated, during which participants will consume liquid meals containing stable isotopes at regular intervals and receive other isotopes intravenously. Meal composition will differ only by fructose content (High vs. Low) and tracer (oral vs. intravenous 13C-labeled fructose). Blood and urine samples will be collected frequently throughout the study. Each visit will be performed approximately three weeks apart. Vital signs and anthropometrics will be measured at each clinic visit.

Inclusion Criteria:

• BMI 30 to 38 kg/m2 (obese group) or BMI 19 to 25 kg/m2 (lean group)

Exclusion Criteria:

• Pregnancy or lactation within the past six months;
• Type 1 or 2 diabetes mellitus (including fasting glucose ≥126 mg/dL, HgbA1c ≥6.5%);
• History of liver disease or AST and ALT 2x above the upper limit of normal;
• Fasting triglyceride > 300 mg/dl; total cholesterol levels above the 95th percentile for age and sex;
• Hemoglobin (Hgb) <12.5g/d or hematocrit<3x Hgb value;
• Report of HIV or hepatitis B or C infection;
• History of cancer, other than basal cell or squamous cell carcinoma or kidney disease stage 3 or higher or patients currently on dialysis;
• Use of any anti-diabetic medications or hypolipidemic agents in the past six months;
• History of surgical procedure for obesity;
• Change in body weight >5% in the past six months (by self-report);
• History of other conditions known to affect insulin sensitivity and lipid metabolism (e.g., polycystic ovary syndrome), history of galactosemia, hereditary fructose intolerance, or who test positive for fructose malabsorption at screening;
• Known intolerance to acetaminophen.

The de-identified clinical and laboratory data set will be made available upon request to academic investigators.

Study data will be made available for at least 5 years from publication of the primary manuscript.

Academic investigators may request data and supporting information upon request to the PI.