Obesity has become a major worldwide health issue over the past few years that can lead to insulin resistance (IR) and type 2 diabetes. Macrophage inflammation in adipose tissue (AT) is thought to contribute to the development of IR in obese individuals. Studies have shown that anti-inflammatory macrophages are more prevalent in lean AT, whereas inflammatory macrophages are more prevalent in obese AT. Many labs have largely focused on recruitment of new macrophages into obese AT as a mechanism of increased AT macrophage (ATM) number. However, retention of macrophages may also serve as a mechanism for their accrual. Interestingly, no one has focused on a defect in ATM apoptosis as a mechanism responsible for retention/accumulation of macrophages in AT. Previous studies demonstrate that ATM apoptosis does occur in obese mice. In addition, preliminary data from our lab suggest that ATMs are more prone to apoptosis in lean compared to obese mice. Determining the mechanisms involved in increased ATM survival in obese mice may lead to the discovery of viable targets for decreasing ATM content. The transcription factor, NF-?B, is involved in mediating pro-survival as well as pro-inflammatory gene expression in many cell types and is expressed in ATMs. Increased NF-?B activation in ATMs could serve as a mediator of their survival in obese mice. Therefore, we hypothesize that NF-?B activation contributes to survival of inflammatory macrophages in obese AT. To determine the role of NF-kB in ATM survival in obese mice, differences in the expression of BCL2 pro-survival proteins and NF-?B activation in ATMs of lean and obese mice will be assessed. In addition, we will determine how inhibition or activation of NF-?B modulates ATM survival in lean and obese mice.

Public Health Relevance

The proposed research will investigate the role of NF-?B in inflammatory adipose tissue macrophage (ATM) survival in obese adipose tissue. ATM inflammation is thought to contribute to the chronic inflammation in obese tissue that ultimately contributes to the development of insulin resistance and type 2 diabetes. Understanding the mechanisms by which NF-?B can help prolong ATM survival could help develop new therapies against these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31DK100144-01
Application #
8596977
Study Section
Special Emphasis Panel (ZDK1-GRB-R (M1))
Program Officer
Mcbryde, Kevin D
Project Start
2013-09-05
Project End
2016-09-04
Budget Start
2013-09-05
Budget End
2014-09-04
Support Year
1
Fiscal Year
2013
Total Cost
$26,592
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Hill, Andrea A; Reid Bolus, W; Hasty, Alyssa H (2014) A decade of progress in adipose tissue macrophage biology. Immunol Rev 262:134-52