There have been many studies linking obesity to the development of Type 2 Diabetes Mellitus. In obesity, a chronic low-grade state of inflammation characterizes the adipose tissue as a result of macrophage infiltration and increased inflammatory cytokine production. This increased macrophage presence has been linked to the development of diabetes and reducing the number of adipose tissue macrophages has also been shown to improve insulin signaling. Osteopontin (OPN) is a glycophosphoprotein that is highly expressed in obese insulin resistant patients and rodents, particularly by macrophages in the adipose tissue. OPN also has chemoattractant properties and acts as a macrophage activator. The goal of this proposal is to target OPN specifically in adipose tissue macrophages, and thus lower the number of macrophages while also effectively reducing inflammation. Studies that involve inhibiting OPN and knockout mice all show an improvement in diet induced insulin resistance. Therefore I hypothesize that by using RNAi to knock down osteopontin in macrophages, I will reduce macrophage infiltration and inflammation, and also improve adipose tissue and liver function.

Public Health Relevance

Type 2 Diabetes is a global epidemic that is rapidly on the rise and understanding how it is linked to obesity will allow us to produce better treatment options. Macrophages infiltrate the adipose tissue of obese individuals, precipitating a chronic low-grade inflammatory state thought to play a critical role in the development of insulin resistance. The work proposed here will study macrophage infiltration and biology so as to determine effective therapeutic strategies to treat and curb the incidence of diabetes.

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 #
5F31DK096948-03
Application #
8668944
Study Section
Special Emphasis Panel (ZDK1-GRB-R (M1))
Program Officer
Mcbryde, Kevin D
Project Start
2012-06-01
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$29,190
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Aouadi, Myriam; Vangala, Pranitha; Yawe, Joseph C et al. (2014) Lipid storage by adipose tissue macrophages regulates systemic glucose tolerance. Am J Physiol Endocrinol Metab 307:E374-83
Aouadi, Myriam; Tencerova, Michaela; Vangala, Pranitha et al. (2013) Gene silencing in adipose tissue macrophages regulates whole-body metabolism in obese mice. Proc Natl Acad Sci U S A 110:8278-83