There is a growing world-wide obesity epidemic that is linked to hyperlipidemia, inflammation, and insulin resistance. The presence of obesity and these down-stream metabolic effects greatly increases the risk of development of diabetes and cardiovascular disease. There are many different factors leading to increased adiposity, with the quantity and composition of dietary fats contributing heavily to this epidemic. Consumption of saturated fatty acids (SFAs) has been shown to be associated with increased risk of atherosclerotic disease as well as IR, while diets rich in polyunsaturated fatty acids (PUFAs) are protective against these conditions. Macrophages, cells of the innate immune system, have been demonstrated to infiltrate white adipose tissue (WAT) in obese rodents and humans. Increased macrophages accumulation in WAT is associated with local and systemic inflammation, and their accumulation has also been shown to temporally precede the development of IR. Thus, adipose tissue macrophages (ATMs) are key mediators of the pathophysiological consequences of obesity. Our preliminary data are consistent with the idea that not only obesity, but also dietary fatty acid composition, can influence macrophage infiltration into WAT, local and systemic inflammation, and IR. Our data are also in support of a role for Toll-like receptor 4 (TLR4) in SFA- induced monocyte migration. Consequently, the overall working hypothesis of this proposal is: SFAs can initiate macrophage recruitment to WAT by both chemokine-dependent and -independent mechanisms and that macrophaqe TLR4 expression mediates this SFA-responsive migration. A corollary to this hypothesis is that PUFAs can blunt SFA-induced macrophage migration. This hypothesis will be tested in three specific aims: (1) To determine whether dietary SFAs promote macrophage infiltration of WAT via increasing adipocyte or ATM chemokine expression, (2) To determine whether SFAs can promote macrophage migration independently of chemokine expression, and (3) To distinguish between TLR4-dependent and -independent processes effecting monocyte recruitment to WAT. We will utilize in vitro methods to determine whether SFAs can act as chemoattractants and whether exposure of monocytes to SFAs increases their migratory potential. In addition, we will use obesity-prone mice to study, in vivo, the effects of dietary fatty acids, fatty acid mobilization in WAT, and macrophage TLR4 expression on ATM accumulation. The clinical consequences of obesity, including diabetes and cardiovascular disease are placing a tremendous burden on our health care system. A better knowledge of mechanisms by which macrophages sense and respond to dietary fatty acids, leading to their recruitment and activation in WAT is imperative for our understanding of their contribution to obesity-related syndromes. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089466-02
Application #
7495617
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2007-09-15
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$383,750
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Orr, Jeb S; Kennedy, Arion J; Hill, Andrea A et al. (2016) CC-chemokine receptor 7 (CCR7) deficiency alters adipose tissue leukocyte populations in mice. Physiol Rep 4:
Bolus, W Reid; Gutierrez, Dario A; Kennedy, Arion J et al. (2015) CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue. J Leukoc Biol 98:467-77
Hasty, Alyssa H; Gutierrez, Dario A (2014) What have we really learned about macrophage recruitment to adipose tissue? Endocrinology 155:12-4
Orr, Jeb S; Kennedy, Arion J; Hasty, Alyssa H (2013) Isolation of adipose tissue immune cells. J Vis Exp :e50707
Anderson, Emily K; Gutierrez, Dario A; Kennedy, Arion et al. (2013) Weight cycling increases T-cell accumulation in adipose tissue and impairs systemic glucose tolerance. Diabetes 62:3180-8
Orr, Jeb S; Puglisi, Michael J; Ellacott, Kate L J et al. (2012) Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages. Diabetes 61:2718-27
Anderson, Emily K; Hill, Andrea A; Hasty, Alyssa H (2012) Stearic acid accumulation in macrophages induces toll-like receptor 4/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis. Arterioscler Thromb Vasc Biol 32:1687-95
Hasty, Alyssa H; Harrison, David G (2012) Endoplasmic reticulum stress and hypertension - a new paradigm? J Clin Invest 122:3859-61
Gutierrez, Dario A; Hasty, Alyssa H (2012) Haematopoietic leptin receptor deficiency does not affect macrophage accumulation in adipose tissue or systemic insulin sensitivity. J Endocrinol 212:343-51
Gutierrez, Dario A; Kennedy, Arion; Orr, Jeb S et al. (2011) Aberrant accumulation of undifferentiated myeloid cells in the adipose tissue of CCR2-deficient mice delays improvements in insulin sensitivity. Diabetes 60:2820-9

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