Obesity increases the risk for developing both diabetes and cardiovascular disease (CVD). Increased adipose tissue inflammation, with increased chemokine and cytokine expression and macrophage accumulation, contributes to adipose tissue dysfunction, insulin resistance, and development of both diabetes and CVD. Using a mouse model of obesity induced by a high-fat (HF) diet rich in saturated fatty acids (SFAs), we made the novel finding that T cells are increased and the chemokine regulated on activation, normal T-cell expressed and secreted (RANTES) and its receptor, CCR5, along with monocyte chemoattractant protein-1 (MCP-1) and receptor CCR2, are upregulated in adipose tissue of obese insulin-resistant mice and in human visceral adipose tissue. Both ?? T cells and ?? T cells are resident in adipose tissue of lean mice. Compared with lean mice, obese mice have a significant increase in ?? T cells but not in ?? T cells in adipose tissue. RANTES and MCP-1 increase in adipose tissue early in the development of adiposity induced by the high-SFA diet. Palmitic acid, a long-chain SFA present in high concentration in the HF diet, increases MCP-1 and RANTES expression in adipocytes in vitro. RANTES and MCP-1 secreted by mouse adipose tissue induce T cell and macrophage migration. Deficiency of ?? T cells in mice decreases adipose tissue inflammation induced by the HF diet. Activated T cells inhibit preadipocyte-to-adipocyte differentiation, with significant reduction of triglyceride accumulation in adipocytes, and also induce adipocyte inflammation. The effects of inflammation on adipose tissue function, such as altered FA metabolism with decreased FA deposition and increased FA release by adipocytes, may increase free FA flux to the liver, cause ectopic fat deposition and increased hepatic and systemic inflammation, and increase the risk for diabetes and CVD. We hypothesize that in the development of adiposity induced by a HF diet, dietary SFAs activate adipose resident cells (adipocytes/preadipocytes, T cells, and macrophages) to produce chemokines that recruit and activate T cells, and that T cells are critical to the progression of inflammatory changes in adipose tissue including recruitment and activation of macrophages. These recruited and activated leukocytes cause pathological adipose tissue dysfunctions (adiposopathy), leading to metabolic abnormalities. To test our hypotheses, we propose the following studies: 1. Determine the direct influence of various fatty acids on chemokine production by resident adipose tissue cells including adipocytes, T cells, and macrophages and determine if this influence results from activation through TLR2 and/or TLR4. 2. Determine the contribution of two prominent chemokine pathways (MCP-1/CCR2 and RANTES/CCR5) to T cell/macrophage recruitment and activation in adipose tissue, and determine the contributions of T cells to the inflammatory process in adipose tissue of mice on a HF diet rich in SFAs. 3. Determine mechanisms by which adipose tissue ?? T cells and/or ?? T cells directly alter preadipocyte or adipocyte functions.

Public Health Relevance

Obesity is becoming a global epidemic in both adults and children and increases the risk for developing both diabetes and cardiovascular disease (CVD). CVD has been shown to be an inflammatory disease, and we hypothesize that obesity caused by a high- calorie, high-fat diet increases the body's inflammatory response. To test our hypothesis, we will study the effects of diet-induced obesity on a number of factors related to inflammation in mice and also in human fat cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078847-04
Application #
8249901
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
2009-05-05
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$320,928
Indirect Cost
$106,126
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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