Sympathetic Activation in Obesity

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

Interventions

DIAGNOSTIC_TEST

PET Scan

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.

DIETARY_SUPPLEMENT

Mixed Meal Test

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.

DIAGNOSTIC_TEST

Muscle sympathetic nerve activity (MSNA)

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.

DIAGNOSTIC_TEST

Oral Glucose Tolerance 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.

OTHER

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

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.

DIAGNOSTIC_TEST

CT Scan

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.

OTHER

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

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.

Sponsors & Collaborators

• National Institutes of Health (NIH)

  collaborator NIH

• Yale University

  lead OTHER

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

45 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2021-11-23

Primary Completion

2022-09-30

Completion

2022-09-30

Countries

• United States

Study Locations