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RESEARCH DESCRIPTION
The growing worldwide obesity epidemic is frequently linked to hyperlipidemia, inflammation, and insulin resistance leading to increased risk of diabetes and cardiovascular disease. The long-term goal of my laboratory is to determine mechanisms by which obesity increases risk for and pathophysiological consequences of these devastating diseases. Macrophages are part of the innate immune system that infiltrate white adipose tissue (WAT) in obese rodents and humans, and produce most of the inflammatory cytokines and chemokines secreted from WAT. In addition, their presence has been shown to be temporally associated with the development of insulin resistance. My current research focus is to determine mechanisms by which macrophages are attracted to WAT. There are three main molecules we are targeting.
Monocyte Inflammatory Protein 1a
Much interest has been generated recently regarding the role of chemoattractant proteins in adipose tissue macrophage accumulation. Chemokines such as monocyte inflammatory protein-1a (MIP-1a) and monocyte chemoattractant protein-1 (MCP-1) are highly expressed in adipose tissue in correlation with the degree of adiposity. Published data indicate that MCP-1 contributes significantly to obesity-induced ATM accumulation; however, nothing is known about the role of MIP-1a in diet induced obesity, macrophage infiltration of WAT insulin resistance, or atherosclerosis.
Saturated Fatty Acids and Toll-Like Receptor 4
Our preliminary data are consistent with the idea that dietary fatty acid composition can influence macrophage infiltration into WAT, local and systemic inflammation, and insulin resistance. Furthermore, we have evidence that these effects can be both chemokine-dependent and -independent. Finally, our data are in support of a role for Toll-like receptor 4 (TLR4) in saturated fatty acid (SFA)-induced monocyte migration. Consequently, we hypothesize that SFAs can initiate macrophage recruitment to WAT by both chemokine-dependent and -independent mechanisms and that macrophage TLR4 expression mediates this SFA-responsive migration. A corollary to this hypothesis is that polyunsaturated fatty acids can blunt SFA-induced macrophage migration.
Leptin
Human obesity is associated with the presence of central leptin resistance leading to hyperleptinemia. The physiologic consequences of elevated plasma leptin levels on peripheral tissues are largely unknown. Recent publications have focused on the role of chemokines such as MCP-1 in the recruitment of monocytes to WAT. We have preliminary data suggesting that leptin is also a potent monocyte/macrophage chemoattractant. Moreover, because adipocytes secrete both leptin and MCP-1, these two molecules could have additive or synergistic effects on monocyte recruitment to WAT. Therefore, we hypothesize: leptin and MCP-1 act, in concert, to initiate monocyte recruitment to WAT leading to downstream physiological consequences such as inflammation and insulin resistance.
Key Words: obesity, inflammation, adipose tissue, macrophage, atherosclerosis, hyperlipidemia, insulin resistance, leptin, macrophage inflammatory protein, fatty acids, nutrition
See our papers that have been highlighted in the Aliqouts Section of the Vanderbilt Reporter
www.mc.vanderbilt.edu/reporter/index.html
www.mc.vanderbilt.edu/reporter/index.html
www.mc.vanderbilt.edu/reporter/index.html
Funding:
- American Diabetes Association Career Development Award (1-07-CD-10)
- NIH R01 HL089466
