Effects of Morbid Obesity and Bariatric Surgery on Brain Inflammation, and Activation of Central Reward System

Effects of Morbid Obesity and Bariatric Surgery on Brain Inflammation, Insulin Resistance and Activation of Central Reward System Studied Using PET- and MRI-imaging

Background: The investigators have found that obesity and insulin resistance result in significantly increased brain insulin-stimulated glucose uptake, whereas in every other tissue glucose uptake is lower in the obese compared to lean individuals. One possible explanation to this could be central inflammation and activation of brain glial cells, which has been shown to occur in animal models of obesity.

Aims: The objective of this study is to investigate whether there is brain inflammation in human obesity, and whether weight loss following bariatric surgery decreases brain inflammation.

Methods: A total of 60 morbidly obese subjects, assigned for Roux-en-Y gastric bypass or for sleeve gastrectomy according to routine treatment protocols will be recruited for this study. A control group of 30 healthy subjects will also be recruited. The following studies will be performed to patients and healthy subjects: 1) structural MRI and MRS, 2) functional MRI, 3) PET imaging of cerebral inflammation and astrocyte activation using [11C]-PK11195, 4) measurement of whole-body and tissue insulin sensitivity by combining hyperinsulinemic, euglycemic clamp with [18F]-FDG-PET, 5) neuropsychological testing. The study procedures will be repeated for the morbidly obese 6 months postoperatively.

This is a prospective study, where subjects for the morbidly obese group (N=60) will be recruited from the patients undergoing bariatric surgery according to normal treatment protocol and the bariatric procedure is decided on clinical data together with the bariatric surgeon and the patient. The morbidly obese patients are studied before and 6 months after bariatric surgery.

Results of obese are compared to results of healthy subjects (N=30), who are studied once.

MRI studies: Brain structural MRI and MRS Structural brain MRI will be performed to obtain anatomical reference. The MR part of a 3T PET-MR system will be used for the study . MR spectroscopy (MRS) will be used to determine levels of different metabolites.Brain activation studies (functional MRI) The aim of the fMRI is to assess how morbid obesity and weight loss influence the brain reward system in response to visual cues (not food related); resting state fMRI will also be performed.

Brain inflammation: [¹¹C]-PK11195 tracer with PET/CT is used to determine activation of glial cells, or inflammation, in the brain. After intravenous injection of 500 MBq [¹¹C]-PK11195, a 60-minute dynamic scan on the brain using the same PET/CT cameras will be performed. Both ROI- and SPM based statistics will be used in the statistical analyses.

Whole-body scan with [18F]-FDG and PET/CT during euglycemic hyperinsulinemia used to promote tissue glucose uptake and measure insulin sensitivity. After 60 minutes from the start of clamp, the subjects will be injected intravenously with 150 MBq of [18F]-fluorodeoxyglucose ([18F]-FDG) Thereafter [18F]-fluorodeoxyglucose uptake in the brain, abdomen, femoral region will be measured.

For the morbidly obese subjects:

1. BMI 35.0-45.0 kg/m2, or BMI 32.0-45.0 kg/m2 and diagnosed diabetes
2. Eligible to bariatric surgery evaluated according to normal treatment paradigm

Exclusion Criteria:

1. Metal objects in the body (including pacemakers, metallic artificial valve prostheses, inner ear implants, surgical clips, braces, foreign fragments)
2. Previous participation in PET studies
3. Pregnancy
4. Poor compliance, alcohol or drug abuse
5. Weight over 150 kg or waist circumference over 150 cm
6. Diabetes with fasting glucose levels ≥7.0 mmol/L, or treatment with insulin
7. Any chronic disease, medication or condition that could create a hazard to subject safety, endanger study procedures or interfere with the interpretation of results.

For the lean control subjects:

Inclusion Criteria:

1. BMI 18-27 kg/m2
2. Fasting plasma glucose ≤6.1 mmol/L
3. Normal values in 2-hour oral glucose tolerance test

Exclusion Criteria:

1. Metal objects in the body (including pacemakers, metallic artificial valve prostheses, inner ear implants, surgical clips, braces, foreign fragments)
2. Previous participation in PET studies
3. Pregnancy
4. Poor compliance, alcohol or drug abuse
5. Smoking
6. History of eating disorders, drastic weight-gain or weight-loss
7. History of psychiatric disorders
8. Any chronic disease, medication or condition that could create a hazard to subject safety, endanger study procedures or interfere with the interpretation of results