Sympathetic Activation in Obesity

NCT04946552 | Completed Results

• 2 other identifiers: 20000307491R56DK129344-01
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this study is to determine whether sympathetic nervous system (SNS) activity in white adipose tissue (WAT) and brown adipose tissue (BAT), skeletal muscle and brain is altered in individuals with obesity in comparison to individuals with normal weight. Simultaneous multi-organ SNS activation will be obtained with a radiotracer for norepinephrine transporter (NET) for whole-body Positron Emission Tomography (PET) imaging and microneurography (peroneal muscle SNS activity). The secondary objectives of this study are: 1) to evaluate whether gender differences affect peripheral SNS in healthy normal weight and obese men and women in adipose tissue (WAT and BAT) and muscle (resting/fasting); 2) To investigate the relationship between peripheral and central SNS activity in obesity, by correlating SNS activity in peripheral tissues (WAT, BAT, and muscle) and brain; and 3) To investigate NET CNS and peripheral SNS activity before and after a high carbohydrate mixed meal in lean and obese men and women.

Conditions

Obesity; Healthy

Outcome Measures

Primary Outcomes (2)

• Distribution Volume Ratio (DVR) of [11C]MRB PET Imaging of Peripheral Sympathetic Nervous System

  Lean individuals with a BMI of 18-25 and obese individuals with a BMI of 30-40 will undergo a PET/CT scan to determine group differences in sympathetic nervous system (SNS) activity in white adipose tissue (WAT), brown adipose tissue (BAT), and deltoid muscle. SNS activity will be determined by using \[11C\]MRB a radiotracer for PET imaging.

  120 minutes

• Microneurography (Muscle Sympathetic Nerve Activity (MSNA)) Measured by Burst Frequency

  Muscle sympathetic nerve activity will be quantified by identification and measurement of sympathetic bursts in the integrated neurogram and expressed as burst frequency (mean number of bursts per unit time) to determinate group differences in peroneal MSNA at baseline (fasting) and during MMT.

  30-60 minutes

Secondary Outcomes (10)

• DVR of Norepinephrine Transporter (NET) in the Central Nervous System (CNS)

  120 minutes

• DVR of [11C]MRB PET Imaging of Peripheral Sympathetic Nervous System After Mixed Meal Test

  120 minutes

• Plasma Glucose

  2 hours

• Insulin Levels

  2 hours

• C-Peptide

  2 hours

Study Arms (2)

Individuals with normal BMI

ACTIVE COMPARATOR

(BMI 18-25 kg/m2)

Diagnostic Test: PET Scan; Dietary Supplement: Mixed Meal Test; Diagnostic Test: Muscle sympathetic nerve activity (MSNA); Diagnostic Test: Oral Glucose Tolerance Test; Other: Body Composition, Percent Body Fat & Percent Body Water (Tanita scale); Diagnostic Test: CT Scan; Other: Body Composition, Percent Body Fat & Percent Body Water (DXA Scan)

Individuals with obesity

ACTIVE COMPARATOR

(BMI 30-40 kg/m2)

Diagnostic Test: PET Scan; Dietary Supplement: Mixed Meal Test; Diagnostic Test: Muscle sympathetic nerve activity (MSNA); Diagnostic Test: Oral Glucose Tolerance Test; Other: Body Composition, Percent Body Fat & Percent Body Water (Tanita scale); Diagnostic Test: CT Scan; Other: Body Composition, Percent Body Fat & Percent Body Water (DXA Scan)

Interventions

PET Scan DIAGNOSTIC_TEST

Participants will come to the PET Center to undergo the whole body \[11C\]MRB PET scan. An intravenous bolus dose of MRB (\~20mCi) will be injected by an infusion pump. PET data will be acquired dynamically for 120 min using the Siemens mCT-X whole-body PET/CT scanner using continuous bed motion to image multiple PET bed acquisitions from the top of the head to the lower abdominal region.

Individuals with normal BMI; Individuals with obesity

Mixed Meal Test DIETARY_SUPPLEMENT

High Carbohydrate Mixed Meal Test (MMT): participants will be studied after a 10-hour overnight fast. A nurse will insert an intravenous (IV) catheter and subjects will ingest a liquid meal (65% carbohydrate, 20% fat, and 15% protein, corresponding to 40% of daily energy expenditure, in \~16 ounces) to be prepared by the Hospital Research Unit Metabolic Kitchen. Blood samples will be collected at -10, 0, 15, 30, 60, 90, and 120 min) for measurement of glucose, insulin and C-peptide concentrations. Plasma samples will be drawn at baseline and throughout the MMT for measurement of additional hormones (such as thyroid hormones, and catecholamines) and free fatty acids (FFA) levels.

Individuals with normal BMI; Individuals with obesity

Muscle sympathetic nerve activity (MSNA) DIAGNOSTIC_TEST

Recording of multiunit postganglionic muscle sympathetic nerve activity (MSNA) will be made from the common peroneal nerve as it winds around the fibular head with the subject in the supine position with the subject's thigh comfortably supported. This procedure requires to first trace the course of the nerve using small electrical stimuli applied to the surface of the skin over the nerve or use of ultrasound to visually assist.

Individuals with normal BMI; Individuals with obesity

Oral Glucose Tolerance Test DIAGNOSTIC_TEST

Following a 10-hour overnight fast, a nurse will insert an intravenous (IV) catheter. Subsequently, subjects will ingest 7.5 oz of Glucola, which contains 75 g of dextrose in orange flavored water. Blood samples will be taken at -15, 0, 10, 20, 30, 60, 90 and 120 minutes (after glucola ingestion) for the measurement of plasma glucose, insulin, and C-peptide concentrations, and calculation of measurements of insulin sensitivity index (Matsuda Index). Approximately 40 mL of blood will be drawn at this visit.

Individuals with normal BMI; Individuals with obesity

Body Composition, Percent Body Fat & Percent Body Water (Tanita scale) OTHER

will be assessed using bioelectrical impedance analysis Tanita® scale; which is a special multi frequency segmental body composition analyzer that delivers a very mild electrical current that allows measurement of fat mass, percent body fat, fat free mass, total body water, and percent body water. This test will be performed at screening visit.

Individuals with normal BMI; Individuals with obesity

CT Scan DIAGNOSTIC_TEST

A CT scan will be performed for attenuation correction and to help delineate the BAT and other regions of interest (ROIs). Images will be reconstructed with an ordered subset expectation maximization algorithm using point spread function correction and time-of-flight information. To delineate fat (WAT, BAT) and skeletal muscle regions of interests (ROIs), CT images are first resliced to match the resolution and location of PET images. As performed in previous studies 2, a supraclavicular ROI is first manually drawn on the CT images. Within that area, the fat ROI is segmented using the CT images and an intensity window from -200 to -50 HU. Subsequently the fat ROI is segmented into WAT and BAT ROIs by using the 11C-MRB PET images: Standardized Uptake Value (SUV) ≥ 1.25 for BAT, SUV \< 1.25 for WAT.

Individuals with normal BMI; Individuals with obesity

Body Composition, Percent Body Fat & Percent Body Water (DXA Scan) OTHER

For better accuracy, measurement of percent fat and percent body water will be obtained with whole body Dual X-Ray Absorptiometry (DXA) scan (Hologic®) on screening-OGTT visit. The scanner arm will move over the participant's body from feet to head. The machine uses a small amount of radiation (one tenth of the amount of radiation from a chest x-ray) to measure body fat, muscle and bone density.

Individuals with normal BMI; Individuals with obesity

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Age 18-45 years
• In good general health as evidenced by medical history and lean (BMI 18.5-24.9 kg/m2) or non-diabetic obese (BMI 30-50 kg/m2) with a fasting plasma glucose (FPG) \<100 mg/dL and a hemoglobin A1c \<5.7%.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Hypertension
• Cardiac or pulmonary disease,
• Known history of Type 1 or Type 2 diabetes
• Hepatic disease, swallowing and gastrointestinal disorders
• Current use of anti-obesity medications, supplements and/or anti-hyperglycemic medications
• Neurological injury or illness, and psychiatric medications
• Women who are pregnant or lactating
• Subjects who suffer from claustrophobia
• Subjects who have received a diagnostic or therapeutic radiopharmaceutical within 7 days prior to participation in this study
• Radiation works or participation in other research studies involving ionizing radiation within one year of the PET scans that would cause the subject to exceed the yearly dose limits.
• Subjects with history of IV drug use which would prevent venous access for PET tracer injection
• Severe motor problems that prevent the subject from lying still for PET and MR imaging
• Subjects who complain of chronic pain
• Blood donation within 8 weeks of the study

Sponsors & Collaborators

• Yale University: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

Church Street Research Unit

New Haven, Connecticut, 06519, United States

Location

MeSH Terms

Conditions

Obesity

Interventions

Positron-Emission Tomography; Glucose Tolerance Test; Body Composition; Tomography, X-Ray Computed; Absorptiometry, Photon

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Tomography, Emission-Computed; Image Interpretation, Computer-Assisted; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Image Enhancement; Photography; Radionuclide Imaging; Tomography; Diagnostic Techniques, Radioisotope; Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques, Endocrine; Investigative Techniques; Biochemical Phenomena; Chemical Phenomena; Metabolism; Body Constitution; Physiological Phenomena; Radiographic Image Enhancement; Radiography; Tomography, X-Ray; Densitometry; Photometry; Chemistry Techniques, Analytical

Results Point of Contact

• Title: Renata Belfort De Aguiar, MD, PhD
• Organization: Yale School of Medicine

renata.aguiar@yale.edu

(203) 785-5331

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2021
• First Posted: July 1, 2021
• Study Start: November 23, 2021
• Primary Completion: September 30, 2022
• Study Completion: September 30, 2022
• Last Updated: February 16, 2024
• Results First Posted: November 9, 2023

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)