The overall goal of this proposal is to develop and evaluate PET imaging methods for measuring activity and distribution (mass) of brown adipose tissue (BAT). This is relevant to the current request for applications: "Human brown adipose tissue: Methods for measurement of mass and activity", RFA-DK-10-002. Type-2 diabetes mellitus, T2DM, previously known as "noninsulin-dependent diabetes mellitus" (NIDDM) or "adult- onset diabetes", is the most common form of diabetes. About 90 to 95 percent of people who have diabetes have T2DM. There are 23.6 million people in the United States, or 8% of the population, who have diabetes. The total prevalence of diabetes increased 13.5% from 2005-2007 according to the American Diabetes Association. BAT has been shown to have thermogenic properties and can reduce white adipose tissue. It may be an important drug target for preventing or treating obesity. Our goal is to develop new imaging methods that will allow measurement of BAT activity and mass. We propose to use the adrenergic system for measuring both activity and distribution (mass) of BAT. The direct involvement of adrenergic system (epinephrine/norepinephrine and ?3 adrenergic receptor) via the uncoupling protein (UCP) in BAT thermogenesis has been reported. The ?3 adrenergic receptor has therefore been pursued as a target for therapeutics development for BAT activation. We propose to investigate two approaches towards activation of BAT using the rodent model by using a ?3-adrenoreceptor agonist, CL 316243 and the norepinephrine transporter (NET) blocker, tomoxetine. Both approaches are expected to stimulate the adrenergic system and increase BAT 18F-FDG in MicroPET/CT imaging. For measuring BAT mass we will develop 11C-CL 316243 as a selective ?3-adrenergic agonist radiotracer for imaging BAT distribution and mass, and also evaluate the NET radiotracer 18F-MFP3 as a potential radiotracer for measuring BAT distribution and mass. One of our goals is to evaluate BAT activity and mass using 18F-FDG and 11C-CL 316243 in the diet-induced obesity rodent model. Radiation dosimetry studies of 11C-CL 316243 will be carried out on rodents for an exploratory Investigational New Drug (eIND) application for translation to human studies. Development of the adrenergic neurotransmitter receptor imaging methods will strongly complement ongoing imaging approaches for obesity and diabetes.

Public Health Relevance

This is a request for developing a noninvasive PET imaging methodology for the study of brown adipose tissue (Good fat). Diabetes is a major health problem currently affecting the US. Increased metabolic activity in the brown fat can accelerate breakdown of white adipose tissue (Bad fat) that is responsible for type 2 diabetes. The proposed research will develop methods to measure the metabolic activity and mass of brown adipose tissue. NOTE: The criteria scores and the critiques given below were provided by the reviewers assigned to this application. These do not necessarily reflect the positions of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers were asked to amend their criteria scores and critiques if their positions changed during the discussion. Please note that the criteria scores are not averaged in arriving at the final overall impact scores. If the reviewers have not changed their criteria scores after the discussion, those shown in the critiques may reflect the opinion of the reviewers before the meeting. The Resume and other initial sections of the summary statement are the authoritative representations of the final outcome of the group discussion. If there is any discrepancy between the reviewers'commentaries and the priority/impact score on the face page of this summary statement, the priority/impact score should be considered the most accurate representation of the final outcome of the group discussion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK092917-02
Application #
8324521
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (M1))
Program Officer
Laughlin, Maren R
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$191,250
Indirect Cost
$66,250
Name
University of California Irvine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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