Neuroimmune Mechanisms in Obesity

Aim 1: To measure levels of microglia using the radiotracer [11C]PBR28 and PET brain imaging in obese (n=50) vs. lean individuals (n=50). The investigators will recruit 100 subjects who will participate in a single [11C]PBR28 scan to measure levels of TSPO, a marker of microglia.

Aim 2: To determine differences in brain functional connectivity at rest and in response to a decision- making task in obese (n=50) vs. lean individuals (n=50) using fMRI imaging. The same subjects from Aim 1 will participate in a resting state functional magnetic resonance imaging (fMRI) followed by a decision making task during fMRI acquisition.

Aim 3: To assess whether acute elevation of lipid levels through intralipid infusion in lean, healthy individuals (n=20) will induce microglial activation. 20 lean individuals will be recruited to participate in a paradigm that includes a baseline [11C]PBR28 scan, an infusion of intralipid, and a second [11C]PBR28 scan approximately 4 hours post intralipid infusion. The investigators will attempt to utilize subjects from aim 1 in order to use their baseline scans for this paradigm.

Aim 4: To determine whether there are differences in levels of microglia between individuals with and without type 1 diabetes (n=20). 20 patients with diabetes (type 1 diabetes or type 2 diabetes)will be recruited to participate in a single [11C]PBR28 scan to compare to Aim 1 participants.

Study Overview

• Status: Withdrawn
• Conditions: Obesity
• Intervention / Treatment: Drug: Intralipid Infusion

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 18-55 years
• Able to read and write English and provide voluntary informed consent
• Physically and psychiatrically healthy by medical history, physical, psychiatric, neurological, EKG and laboratory examinations
• For Aims 1-3: HbA1C < 5.7%
• For Aim 4: HbA1C >6.5% and known diagnosis of T1DM or T2DM

Exclusion Criteria:

• Abnormal labs including Creatinine>1.5mg/dL, Hematocrit < 35% for females and < 39% for males, ALT/AST >2.5X upper limit of normal, abnormal TSH
• Known significant thyroid, hepatic, neurologic, psychiatric, cerebrovascular, or cardiovascular disease
• >5% body weight change in last 6 months
• Current or recent regular steroid use in last 6 months, illicit drug use that is deemed to interfere with results including problematic alcohol use as defined by NIAAA
• Current regular use of psychotropic and/or potentially psychoactive prescription medications
• Regular use of any vitamins/supplements that could affect lipids
• Current regular use of non-steroidal anti-inflammatory medications, statins, or lipid lowering agents
• Vaccination in the last month
• Individuals who are classified as "low binders" for the rs6971 polymorphism (<10% of the population)
• For females, physical or laboratory (-HCG) evidence of pregnancy, seeking pregnancy, or lactating. A urine drug screen and pregnancy test will be performed at screening and prior to the imaging session. Subjects who screen positive will be excluded.

Note: If a subject tests positive for an illicit substance, the PI will determine if the substance would interfere with the results and may terminate participation if applicable. Results of the test would only be noted in the subjects de-identified chart to document the occurrence.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Baseline [11C]PBR28 PET Scan; Subjects will complete a 120-minute baseline [11C]PBR28 PET scan.
Experimental: Post-Intralipid Infusion [11C]PBR28 PET Scan; Subjects will complete a second 120-minute [11C]PBR28 PET scan 4 hours after Intralipid Infusion	Drug: Intralipid Infusion; Intralipid 20% (a 20% IV fat emulsion) is a sterile, non-pyrogenic fat emulsion prepared for IV administration as a source of calories and essential fatty acids. It is made up of 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin and water for injection. In addition, sodium hydroxide has been added to adjust the pH so that the final product pH is 8.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline [11C]PBR28 VT values	[11C]PBR28 VT values in our primary regions of interest (PFC and hippocampus) from PET Scan. Linear mixed-effect models will be conducted to evaluate differences in [11C]PBR28 VT values between lean, healthy controls (n=40) and individuals with obesity (n=40), controlling for rs6971 genotype, age, and sex.	At baseline
Post-Intralipid [11C]PBR28 VT values	[11C]PBR28 VT values in our primary regions of interest (PFC and hippocampus) from PET Scan. Linear mixed-effect models will be conducted to evaluate differences in [11C]PBR28 VT values between lean, healthy controls (n=40) and individuals with obesity (n=40), controlling for rs6971 genotype, age, and sex.	Approximately 3 Hours After Intralipid Infusion
Baseline Functional Connectivity	ICD values will be obtained from primary a priori regions of interest (vmPFC and hippocampus) with PET Scan. Independent t-tests will be used to compare the ICD data between the study groups.	At baseline
Post-Intralipid Functional Connectivity	ICD values will be obtained from primary a priori regions of interest (vmPFC and hippocampus) with PET Scan. Independent t-tests will be used to compare the ICD data between the study groups.	Approximately 3 Hours After Intralipid Infusion
Baseline Microglial Activation	Regional [11C]PBR28 VT values from pre-lipid infusion PET Scan	At baseline
Post-Intralipid Microglial Activation	Percent change in regional [11C]PBR28 VT values from pre-lipid infusion PET Scan to post-lipid infusion PET Scan will be calculated across brain regions. Increased microglial activation will be measured as a 20% or more increase in TSPO levels from scan 1 to scan 2	Approximately 3 Hours After Intralipid Infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Visual Attention	Visual attention: response latency to identify card color (log10(ms); higher ~ worse attention).	At baseline
Post-Intralipid Infusion Visual Attention	Visual attention: response latency to identify card color (log10(ms); higher ~ worse attention).	Approximately 1 Hour After Intralipid Infusion
Baseline Visual Learning	Visual learning: % of correctly identified repeat cards (arcsine(% correct); higher values ~ better learning).	At baseline
Post-Intralipid Infusion Visual Learning	Visual learning: % of correctly identified repeat cards (arcsine(% correct); higher values ~ better learning).	Approximately 1 Hour After Intralipid Infusion
Baseline Verbal Memory	Verbal memory: # of correctly recalled items from a grocery list (3 trials). Verbal recall: # of correctly recalled items from a grocery list after a delay (1 trial; higher ~ better memory/recall).	At baseline
Post-Intralipid Verbal Memory	Verbal memory: # of correctly recalled items from a grocery list (3 trials). Verbal recall: # of correctly recalled items from a grocery list after a delay (1 trial; higher ~ better memory/recall).	Approximately 1 Hour After Intralipid Infusion
Baseline Executive Function	Executive function: number of errors navigating a 'hidden' maze (5 trials; higher ~ worse executive function).	At baseline
Post-Intralipid Executive Function	Executive function: number of errors navigating a 'hidden' maze (5 trials; higher ~ worse executive function).	Approximately 1 Hour After Intralipid Infusion
Baseline Visual-Motor Processing Speed	Visual-motor processing speed: response latency to detect a card flipped over (log10(ms); higher ~ worse processing speed).	At baseline
Post-Intralipid Visual-Motor Processing Speed	Visual-motor processing speed: response latency to detect a card flipped over (log10(ms); higher ~ worse processing speed).	Approximately 1 Hour After Intralipid Infusion
Baseline Working Memory	Working memory: % of correctly identified cards that matched the card presented either one- or two-cards previously (arcsine(% correct); higher ~ better working memory).	At baseline
Post-Intralipid Working Memory	Working memory: % of correctly identified cards that matched the card presented either one- or two-cards previously (arcsine(% correct); higher ~ better working memory).	Approximately 1 Hour After Intralipid Infusion
Baseline Social Cognition	Social cognition: response latency to identify the mismatched facial expression based on its emotional content (ms; log10; higher ~ worse social cognition).	At baseline
Post-Intralipid Social Cognition	Social cognition: response latency to identify the mismatched facial expression based on its emotional content (ms; log10; higher ~ worse social cognition).	Approximately 1 Hour After Intralipid Infusion
Baseline Reward Responsiveness	Reward responsiveness will be quantified via computerized Probabilistic Reward Task	At baseline
Post-Intralipid Reward Responsiveness	Reward responsiveness will be quantified via computerized Probabilistic Reward Task	Approximately 1 Hour After Intralipid Infusion

Collaborators and Investigators

• Sponsor: Yale University
• Investigators: Principal Investigator: Kelly Cosgrove, PhD, Yale University

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): January 1, 2033
• Study Completion (Estimated): January 1, 2033

Study Registration Dates

• First Submitted: September 20, 2022
• First Submitted That Met QC Criteria: September 20, 2022
• First Posted (Actual): September 23, 2022

Study Record Updates

• Last Update Posted (Estimated): June 16, 2023
• Last Update Submitted That Met QC Criteria: June 15, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Soybean oil, phospholipid emulsion
• Other Study ID Numbers: 2000031993

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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