Neuroimaging Study. Male and Female volunteers will be recruited from the Investigational Weight Management Clinic (IWMC) at the University of Michigan for this study. All neuropsychological instruments will be collected in lean and obese individuals at baseline, and between 4-6-months. Obese individuals will undergo 4 PET scans: 1) at baseline following an overnight fast; 2) at baseline following consumption of an Ensure shake; 3) after at least a15% reduction in body weight following an overnight fast; 4) and following consumption of an Ensure shake at the post-weight loss time point. Lean individuals will undergo the two scans at baseline after fasting and post-Ensure shake consumption. All lean subjects will consume their normal diets prior to the initial scanning. The obese subjects will undergo their second set of scans, post-weight loss, while still consuming the HMR diet.

Neuroimaging Measures. Two PET studies with \[11C\]carfentanil (a selective µ-opioid receptor radiotracer) will be acquired for each lean volunteer and 4 PET studies with \[11C\]carfentanil will be acquired for obese individuals. Structural and functional MRI will be acquired for obese individuals before and after weight loss, and for lean individuals at baseline for co-registration and anatomical standardization of the PET data and activation response to visual stimuli. After their completion, the following data will be used for statistical analyses: 1) Baseline µ-opioid receptor availability in vivo (binding potential, BPND) in lean and obese individuals following an overnight fast. 2) µ-opioid system activation after consuming 500 kcal (16fl oz, 18% protein, 14% CHO, 25% fat) of Ensure shake (fed) in lean and obese individuals as measured by acute reductions in BPND. 3) Baseline MOR BPND in obese individuals who have lost ≥15% of their body weight over 4-6 months (fasting), following an overnight fast. 4) µ-opioid system activation in obese individuals who have lost ≥15% of their body weight after consuming 250 kcal of Ensure shake (fed).

PET Acquisition. Briefly, \[11C\]carfentanil a selective and specific µ-opioid receptor radioligand, is administered at tracer doses using a bolus/continuous infusion protocol to achieve rapid steady-states between specific and non-specific binding regions (5-7 min post-tracer administration). Twenty-eight frames will be acquired over 70 minutes with an increasing duration (30 sec to 5 min). Two scans will be acquired twice each: A baseline, without challenges, and a scan following consumption of an Ensure shake. Subsequently, dynamic image data for the receptor scans is transformed, on a voxel-by-voxel basis, into parametric maps, and co-registered to each other. These include, 1) a tracer transport measure (K1 ratio, proportional to cerebral blood flow; tracer transport = blood flow x tracer extraction), and receptor-related measures, (BPND), during 2) baseline scans, and 3) following shake consumption. The reduction in BPND from baseline to post-shake consumption represents a measure of endogenous opioid system activation following shake consumption (related to the occupancy and ligand-receptor interactions by the endogenous ligand). These parametric images are calculated using a modified Logan graphical analysis, with the occipital cortex as the reference region. PET images are then co-registered to the T1 MRI structural, anatomical image, affine transformed and warped to standard Montreal Neurological Institute (MNI) stereotactic space using mutual information algorithms. The baseline scan, in the fasted state, will precede the post-consumption scan due to time constraints, and to avoid carry-over effects from active (fed) to baseline (fasted) states. Both PET scans will be performed on the same day to reduce travel time for the subjects and hence experimental burden.

Clinical Measures Psychobehavioral measures to be acquired during the imaging studies include: The Positive and Negative Affect Scale, Profile of Mood Scales, State portion of the Spielberg Anxiety Inventory, and a visual analog scale (VAS) for appetite and palatability will be administered before and after each experiment. These measures will assess emotional state and appetite for correlative purposes with changes in neuroreceptor and circulating hormone levels during performance of the studies. The MINI International Neuropsychiatric Interview (MINI600), Inventory of Depressive Symptomatology (IDS-SR), EuroQol measure of health outcome, Trait portion of the Anxiety Inventory, and NEO Personality Inventory will be obtained prior to scanning for secondary analyses (e.g. relationship between imaging measures and "stable" traits).