Obesity-induced inflammation is a contributing factor in the pathogenesis of insulin resistance and Type 2 diabetes. Both adipose tissue macrophages (ATMs) and adipose tissue T cells (ATTs) accumulate during obesity. ATMs and ATTs produce pro-inflammatory signals that impair insulin action in adipose tissue. However, a clear understanding of how ATTs and ATMs communicate to initiate and sustain adipose tissue inflammation and generate insulin resistance during obesity is lacking. Our group is exploring the hypothesis that communication between ATMs and ATTs in adipose tissue is central to shaping the inflammatory environment in fat. We have found that CD40 expression is increased in visceral fat during diet-induced obesity and that ATMs express CD40. CD40 is a transmembrane glycoprotein belonging to the TNF receptor superfamily. The ligand for CD40, CD40L (or CD154), is highly expressed on activated T lymphocytes. CD40- CD40L signaling has been shown to be critical for T cell priming, effector function, and initiation of T cell- mediated immunity. Our preliminary data support a model in which signals derived from high fat diet exposure induce CD40 on ATMs to promote activation and expansion of CD4+ ATTs. The central hypothesis of this application is that the CD40-CD40L pathway mediates communication between ATMs and ATTs to promote ATM activation to drive expansion of antigen-specific CD4+ ATTs and induce inflammation and insulin resistance during obesity. The goal of this training proposal is for the trainee to rigorously test this model while learning and applying immunology techniques to measure ATM function and ATT responses in cultured cells and in fat.
In Aim 1, we will determine how CD40 expression in ATMs is regulated by adipocytes. Specifically, we will test the working hypothesis that adipocyte hypertrophy and death activates TLR4 and NF-:B signaling pathways in ATMs to induce CD40 expression.
In Aim 2, we will examine the effects of CD40 activation on the biology of M1 and M2 ATMs. The proposed experiments will test whether CD40 activation induced maturation and cytokine production by ATMs, and whether CD40 activation participates in the regulation of ATTs by ATMs.
In Aim 3, we will test the working hypothesis that CD40 activation in leukocytes is principally responsible for the generation of inflammatory signals in visceral fat during obesity. The proposed experiments will provide a clear understanding as to whether and how CD40-CD40L signaling contributes to obesity- induced inflammation. The training proposal is specifically designed to promote cross training in the fields of immunology and metabolism. The trainee will develop expertise in ATM biology and regulation of obesity- induced inflammation, learn key immunological concepts relevant to the regulation of ATMs and ATTs, and receive training in state of the art techniques used by immunologists and obesity researchers.

Public Health Relevance

Obesity activates immune cells in fat tissue, which contributes to the development of insulin resistance and metabolic disease. This proposal will investigate how obesity affects communication between two important inflammatory cells, macrophages and T cells, in fat tissue. Results from this study could lead to the development of novel therapies for metabolic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32DK091976-02
Application #
8265988
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (J1))
Program Officer
Castle, Arthur
Project Start
2011-02-18
Project End
2014-02-17
Budget Start
2012-02-18
Budget End
2013-02-17
Support Year
2
Fiscal Year
2012
Total Cost
$52,190
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Cho, Kae Won; Morris, David L; Lumeng, Carey N (2014) Flow cytometry analyses of adipose tissue macrophages. Methods Enzymol 537:297-314
Su, Hsiao-Wen; Lanning, Nathan J; Morris, David L et al. (2013) Phosphorylation of the adaptor protein SH2B1? regulates its ability to enhance growth hormone-dependent macrophage motility. J Cell Sci 126:1733-43
Morris, David L; Cho, Kae Won; Delproposto, Jennifer L et al. (2013) Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes 62:2762-72
Morris, David L; Oatmen, Kelsie E; Wang, Tianyi et al. (2012) CX3CR1 deficiency does not influence trafficking of adipose tissue macrophages in mice with diet-induced obesity. Obesity (Silver Spring) 20:1189-99
Morris, David L; Singer, Kanakadurga; Lumeng, Carey N (2011) Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. Curr Opin Clin Nutr Metab Care 14:341-6