This project will be a three-group controlled 6-wk feeding study where all meals are prepared and provided to obese participants. All participants will be fed a 25% energy-restricted diet. Two diets will be very low in carbohydrate (i.e., ketogenic diets) designed to induce nutritional ketosis and fat loss. Another diet will be low in fat and saturated fat but contain the same total calories. Participants will be randomly assigned to a Ketone Supplement group (n=12) who are provided an exogenous pre-formed source of beta-hydroxybutyrate (BOHB) or a Control group (n=12) that only receives the standard ketogenic diet. Randomization will be stratified based on insulin resistance, sex, and body composition to ensure balanced group assignment. Because of timing of recruitment (i.e., after most of the ketogenic groups have already completed the study), the low-fat group will not be randomized. Outcome measurements will be made at various intervals over the 6-wk intervention. Key outcome variables will include: 1) Markers of Ketosis/Keto-Adaptation: a. Daily measures of BOHB (capillary blood) b. Fasting serum BOHB and total ketones (venous blood) c. Diurnal capillary blood ketones and urinary loss of BOHB and total ketones 2) Energy Balance and Body Composition: a. Body mass (scale) b. Whole body and regional composition (DXA) c. Nitrogen balance (daily nitrogen intake - 24-hr urinary nitrogen loss) d. Resting energy expenditure and substrate oxidation (indirect calorimetry) e. Adiposity (myocardial/epicardial fat, liver fat, visceral fat, skeletal muscle fat by MRI) f. Microbiome (stool collection to observe microbiota and the response to diet alteration) 3) Cognitive and Behavioral: a. Computer-based cognitive function (ANAM) b. Behavioral responses (surveys) 4) Cardio-Metabolic Risk: a. Metabolic panel b. Circulating lipid panel (total cholesterol, LDL-C, HDL-C, TG) c. Glucose, insulin, HOMA
