Effects of Morbid Obesity and Bariatric Surgery on Brain Inflammation, Insulin Resistance and Central Reward System (BariBrainPET)

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: Morbid obesity is associated with decreased brain µ-opioid receptor availability, possibly resulting in higher food intake needed to gain pleasure from eating. This decrease seems to normalize already 6 months after bariatric surgery, but the longer-term effects have not been studied. Obesity and insulin resistance result in significantly increased brain insulin-stimulated glucose uptake, whereas in every other tissue glucose uptake is lower. 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. Obesity has also been shown to associate with increased risk of Alzheimer's disease and cognitive decline in several studies.

Aims: The first objective of this study is to both study the effects of bariatric surgery as well as compare the effects of gastric bypass and sleeve gastrectomy on food-associated pleasure, extending the follow-up period to 2 years postoperatively. The second aim is to investigate the effect of morbid obesity and weight loss on brain inflammation and gliosis and its association with increased brain insulin-stimulated glucose uptake. Furthermore, association of obesity, insulin resistance, central inflammation and neurocognitive dysfunction are evaluated.

Study Overview

• Status: Active, not recruiting
• Conditions: Insulin Resistance; Obesity, Morbid
• Intervention / Treatment: Procedure: Bariatric surgery

Detailed Description

Methods: A total of 60 morbidly obese subjects, 30 assigned for Roux-en-Y gastric bypass and 30 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. We will perform 1) structural MRI and MRS, 2) functional MRI during tasting and visual food cues, 3) PET imaging of µ-opioid receptor availability using [11C]-carfentanil, 4) PET imaging of cerebral inflammation and astrocyte activation using [11C]-PK11195, 5) measurement of whole-body and tissue insulin sensitivity by combining hyperinsulinemic, euglycemic clamp with [18F]-FDG-PET, 6) neuropsychological testing. The control group will only be studied once, whereas study procedures will be repeated for the morbidly obese before very-low calorie diet and 6, 12 and 24 months postoperatively.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Turku, Finland, 20520
    • Turku PET Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

Morbidly obese group

1. BMI 35.0-45.0 kg/m2, or BMI 32.0-45.0 kg/m2 and diagnosed diabetes
2. Age 18-60 years
3. Eligible to bariatric surgery evaluated according to normal treatment paradigm

Non-obese controls

1. BMI 18-27 kg/m2
2. Age 18-60 years
3. Fasting plasma glucose ≤6.1 mmol/L
4. Normal values in 2-hour oral glucose tolerance test

Exclusion criteria:

Morbidly obese group

1. Metal objects in the body (including pacemakers, metallic artificial valve prostheses, inner ear implants, surgical clipses, 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.

Non-obese controls

1. Metal objects in the body (including pacemakers, metallic artificial valve prostheses, inner ear implants, surgical clipses, 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Morbidly obese subjects; Bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy)	Procedure: Bariatric surgery; Roux-en-Y gastric bypass or sleeve gastrectomy, chosen based on routine evaluation process; Other Names: Sleeve gastrectomy; Roux-en-Y gastric bypass
No Intervention: Control subjects; Non-obese controls are only studied at baseline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in central inflammation	Assessment of brain glial cell activation using [11C]-PK11195 tracer and positron emission tomography	Controls: 0 months; Morbidly obese: preoperatively, 6 months postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in central reward system using fMRI imaging	Assessment of brain reward system activation after visual/taste cues using functional MRI	Controls: 0 months; Morbidly obese: preoperatively, 6 months, 12 months, 24 months postoperatively
Changes in brain μ-opioid receptor availability using PET imaging	Assessment of brain μ-opioid receptor availability using [11C]-carfentanil tracer and positron emission tomography	Controls: 0 months; Morbidly obese: preoperatively, 6 months, 12 months postoperatively
Changes in cognitive function studied with testing	Neuropsychological testing focusing on memory, decision-making and inhibition	Controls: 0 months; Morbidly obese: preoperatively, 6 months, 12 months, 24 months postoperatively
Changes in whole-body insulin sensitivity usign FDG-PET imaging	Assessment of whole-body insulin sensitivity using hyperinsulinemic, euglycemic clamp	Controls: 0 months; Morbidly obese: preoperatively, 6 months postoperatively
Changes in tissue-specific insulin sensitivity using FDG-PET imaging	Assessment of insulin-stimulated glucose uptake in the brain, liver, skeletal muscle and adipose tissue by performing positron emission tomography with [18F]-fluorodeoxyglucose tracer during hyperinsulinemic, euglycemic clamp	Controls: 0 months; Morbidly obese: preoperatively

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Investigators: Principal Investigator: Pirjo Nuutila, MD, PhD, Turku University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2019
• Primary Completion (Actual): October 10, 2021
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: June 6, 2018
• First Submitted That Met QC Criteria: October 12, 2021
• First Posted (Actual): October 15, 2021

Study Record Updates

• Last Update Posted (Actual): October 15, 2021
• Last Update Submitted That Met QC Criteria: October 12, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: obesity; bariatric surgery; insulin resistance; central nervous system inflammation
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infections; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Central Nervous System Infections; Hyperinsulinism; Obesity; Encephalitis; Inflammation; Insulin Resistance; Obesity, Morbid; Infectious Encephalitis
• Other Study ID Numbers: BariBrain-PET; T153/2018 (Other Identifier: The Hospital District of Southwest Finland)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Under preparation.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No