Adipose tissue inflammation is associated with insulin resistance and an increased risk of cardiovascular disease. Excess dietary saturated fatty acids (SFA) such as palmitate stimulate the production of reactive oxygen species (ROS) by a NOX4-dependent mitochondria-independent pathway, and increase the generation of monocyte chemotactic factors and inflammatory signals in adipocytes. Conversely, an isomer of conjugated linoleic acid (CLA) that is used as a weight loss supplement, decreases triglyceride accumulation and stimulates ROS production by mitochondria rather than NOX4. This too leads to adipocyte chemotactic factor generation and inflammation. On the basis of our preliminary data, we hypothesize that SFA such as palmitate stimulate adipose tissue inflammation by NOX4-dependent generation of ROS by adipocytes. This process involves transfer of key cellular proteins such as NOX4 to the plasma membrane, and can be blocked by removing cholesterol from plasma membranes by exposure to HDL. Conversely, we hypothesize that CLA stimulates adipose tissue inflammation by a distinct pathway that involves generation of ROS by mitochondria, is associated with reduced triglyceride accumulation in adipocytes, is not associated with translocation of proteins to the cell membrane, and is not blocked by HDL. To determine whether NOX expression by adipocytes is required for SFA-induced adipose tissue inflammation, we will specifically delete NOX4 in adipocytes. We also will determine mechanisms by which HDL and its major apolipoprotein, apoA-I, exert anti-inflammatory effects on adipocytes and adipose tissue in vitro and in vivo. Our in vivo studies will focus on the role o the cholesterol transporter, ABCG1, which we have shown in preliminary data to be a likely candidate for the removal of cholesterol from plasma membranes. Since ABCG1 is likely to be produced by adipose tissue macrophages rather than adipocytes, we will transplant either wild type or ABCG1-deficient bone marrow into apoA-I transgenic mice, in which SFA-mediated adipose tissue inflammation is blunted. We will identify differences in how adipocytes metabolize CLA versus palmitate, and determine why CLA leads to triglyceride reduction and fatty acid utilization by mitochondria rather than storage of triglycerides as occurs with other SFA. We also will investigate how this metabolic switch is linked to the generation of mitochondrial ROS, chemotactic factors and inflammatory molecules. Findings from this grant have important implications for preventing diet-induced adipose tissue inflammation and the accompanying insulin resistance and cardiovascular disease risk.

Public Health Relevance

Adipose tissue inflammation is associated with insulin resistance and an increased risk of cardiovascular disease. This study will compare pro-inflammatory effects of two dietary fatty acids that occur by distinct mechanisms, both of which may be harmful. Findings from this study have important implications for preventing diet-induced adipose tissue inflammation and the accompanying insulin resistance and cardiovascular disease risk.

Agency
National Institute of Health (NIH)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56HL094352-05A1
Application #
8903548
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Ershow, Abby
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195