T Cells, Macrophages, Chemokines, and Adiposopathy in Diet-Induced Obesity

Summary

Principal Investigator: CHRISTIE MITCHELL BALLANTYNE
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2009-05-05 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. pmc Tlr2 is critical for diet-induced metabolic syndrome in a murine model
    Ryan W Himes
    Texas Children s Hospital, Section of Pediatric Gastroenterology, 1102 Bates St, Texas Children s Feigin Center, Rm 860B, Houston, TX, 77030, USA
    FASEB J 24:731-9. 2010
  2. pmc CD11c expression in adipose tissue and blood and its role in diet-induced obesity
    Huaizhu Wu
    Section of Atherosclerosis and Vascular Medicine, Baylor College of Medicine, Houston, Tex 77030, USA
    Arterioscler Thromb Vasc Biol 30:186-92. 2010
  3. pmc Effect of the cannabinoid receptor-1 antagonist rimonabant on inflammation in mice with diet-induced obesity
    Qun Wang
    Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, Texas, USA
    Obesity (Silver Spring) 19:505-13. 2011
  4. pmc CD11c/CD18 expression is upregulated on blood monocytes during hypertriglyceridemia and enhances adhesion to vascular cell adhesion molecule-1
    R Michael Gower
    Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
    Arterioscler Thromb Vasc Biol 31:160-6. 2011
  5. pmc Differential effect of weight loss with low-fat diet or high-fat diet restriction on inflammation in the liver and adipose tissue of mice with diet-induced obesity
    Qun Wang
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin, M S A 601, Houston, TX 77030, USA
    Atherosclerosis 219:100-8. 2011
  6. pmc ApoE and the role of very low density lipoproteins in adipose tissue inflammation
    Jiali Wang
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin, M S A 601, Houston, TX 77030, USA
    Atherosclerosis 223:342-9. 2012
  7. pmc Attenuated adipose tissue and skeletal muscle inflammation in obese mice with combined CD4+ and CD8+ T cell deficiency
    Ilvira M Khan
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
    Atherosclerosis 233:419-28. 2014

Detail Information

Publications8

  1. pmc Tlr2 is critical for diet-induced metabolic syndrome in a murine model
    Ryan W Himes
    Texas Children s Hospital, Section of Pediatric Gastroenterology, 1102 Bates St, Texas Children s Feigin Center, Rm 860B, Houston, TX, 77030, USA
    FASEB J 24:731-9. 2010
    ..Himes, R. W., Smith, C. W. Tlr2 is critical for diet-induced metabolic syndrome in a murine model...
  2. pmc CD11c expression in adipose tissue and blood and its role in diet-induced obesity
    Huaizhu Wu
    Section of Atherosclerosis and Vascular Medicine, Baylor College of Medicine, Houston, Tex 77030, USA
    Arterioscler Thromb Vasc Biol 30:186-92. 2010
    ..To examine CD11c, a beta(2)-integrin, on adipose tissue (AT) leukocytes and blood monocytes and its role in diet-induced obesity...
  3. pmc Effect of the cannabinoid receptor-1 antagonist rimonabant on inflammation in mice with diet-induced obesity
    Qun Wang
    Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, Texas, USA
    Obesity (Silver Spring) 19:505-13. 2011
    ..Thus, rimonabant induced weight loss in obese mice by diet-intake-dependent and -independent fashions. Rimonabant decreased inflammation in obese mice, possibly through a primary effect on weight reduction...
  4. pmc CD11c/CD18 expression is upregulated on blood monocytes during hypertriglyceridemia and enhances adhesion to vascular cell adhesion molecule-1
    R Michael Gower
    Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
    Arterioscler Thromb Vasc Biol 31:160-6. 2011
    ..Involvement of β(2)-integrin CD11c/CD18 in atherogenesis was recently shown in dyslipidemic mice, which motivates our study of its inflammatory function during hypertriglyceridemia in humans...
  5. pmc Differential effect of weight loss with low-fat diet or high-fat diet restriction on inflammation in the liver and adipose tissue of mice with diet-induced obesity
    Qun Wang
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin, M S A 601, Houston, TX 77030, USA
    Atherosclerosis 219:100-8. 2011
    ..We studied the effects of weight loss induced by either a low-fat normal diet (ND) or restriction of high-fat diet (HFD) on hepatic steatosis, inflammation in the liver and adipose tissue (AT), and blood monocytes of obese mice...
  6. pmc ApoE and the role of very low density lipoproteins in adipose tissue inflammation
    Jiali Wang
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin, M S A 601, Houston, TX 77030, USA
    Atherosclerosis 223:342-9. 2012
    ..To identify the role of triglyceride-rich lipoproteins (TGRLs) and apoE, a major apolipoprotein in TGRLs, in adipose tissue inflammation with high-fat diet (HFD)-induced obesity...
  7. pmc Attenuated adipose tissue and skeletal muscle inflammation in obese mice with combined CD4+ and CD8+ T cell deficiency
    Ilvira M Khan
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
    Atherosclerosis 233:419-28. 2014
    ..Furthermore, we investigated whether CD4+IFNγ+ (TH1) cells are involved in skeletal muscle and adipose tissue metabolic dysfunction that accompanies obesity...

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  3. Ectopic adiposity in black men with high type 2 diabetes risk
    Iva Miljkovic; Fiscal Year: 2013
    ..The proposed study will greatly advance our understanding of ectopic adiposity and its role in T2D among high risk black men. ..
  4. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  5. Role of the Interleukin12/STAT4 Pathway in Insulin Resistance and Atherosclerosis
    Jerry L Nadler; Fiscal Year: 2013
    ..The completed project should identify an innovative therapeutic target that could lead to new treatment to reduce atherosclerosis associated with central obesity insulin resistance and diabetes. ..
  6. Mechanisms of Renal Lipotoxicity and Injury in Obesity and Diabetes
    Jesus H Dominguez; Fiscal Year: 2013
    ..This is one of the major problems in diabetes- obesity that afflicts our veteran's population. ..
  7. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  8. Role of stearoyl CoA desaturase-1 in TLR5 KO mice colitis and metabolic syndrome
    Matam Vijay Kumar; Fiscal Year: 2013
    ..Overall, our research proposal may help in designing oleate-rich dietary formulations and also clarify whether SCD-1 can be targeted to prevent colitis and metabolic diseases ! ..
  9. Myeloid-specific Triacylglycerol Storage in Inflammation and Metabolic Disease
    SUNEIL KRISHNA KOLIWAD; Fiscal Year: 2013
    ..We propose here to do so in the liver, by determining the role of MC-specific TG storage in the progression of fatty liver disease to liver inflammation and insulin resistance. ..
  10. Inflammation, Insulin Resistance, and Foxo factors
    Stephen M Hedrick; Fiscal Year: 2013
    ..These experiments will greatly enhance our knowledge of the interface between organismal metabolism and the immune system. ..
  11. EXPANDING THE APPLICATION OF MRI FOR BODY FAT STUDIES IN HUMANS
    Houchun H Hu; Fiscal Year: 2013
    ..This project will contribute novel and non-invasive magnetic resonance imaging techniques to accurately and reliably study fat across the entire human body. ..
  12. Monocyte activation and the role of CD11c in obesity-linked metabolic syndrome
    Huaizhu Wu; Fiscal Year: 2013
    ..This study has the potential to provide novel preventive and therapeutic targets for obesity-related atherosclerosis and diabetes. ..
  13. The Role of Visceral Fatty Acids in Relation to Insulin Resistance
    Michelle T Foster; Fiscal Year: 2013
    ..The goal of this proposal is to determine the link between adipocyte expansion and FA retention in the visceral bed and insulin resistance/glucose intolerance. ..
  14. Alterations in Adipocyte Lipid Metabolism by Trans-10, Cis-12 CLA Supplementation
    LAURA JANE DEN HARTIGH; Fiscal Year: 2013
    ....