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Title: Toll Like Receptor-4 Mediates Vascular Inflammation and Insulin Resistance in Diet-Induced Obesity

Author
item KIM, FRANCIS - UNIV OF WASH - SEATTLE
item PHAM, MATILDA - UNIV OF WASH - SEATTLE
item LUTTRELL, IAN - UNIV OF WASH - SEATTLE
item Bannerman, Douglas
item TUPPER, JOAN - UNIV OF WASH - SEATTLE
item THALER, JOSHUA - UNIV OF WASH - SEATTLE
item HAWN, THOMAS - UNIV OF WASH - SEATTLE
item RAINES, ELAINE - UNIV OF WASH - SEATTLE
item SCHWARTZ, MICHAEL - UNIV OF WASH - SEATTLE

Submitted to: Circulation Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/23/2007
Publication Date: 6/7/2007
Citation: Kim, F., Pham, M., Luttrell, I., Bannerman, D.D., Tupper, J., Thaler, J., Hawn, T.R., Raines, E.W., Schwartz, M.W. 2007. Toll Like Receptor-4 Mediates Vascular Inflammation and Insulin Resistance in Diet-Induced Obesity. Circulation Research. 100(11):1589-1596.

Interpretive Summary: The current study identifies a role for Toll-like receptor-4 (TLR-4) signaling in the pathogenesis of vascular inflammation that accompanies such metabolic disorders as diabetes and obesity. These findings have implications beyond these diseases to include such metabolic disorders of cattle as ketosis. TLR-4 is known for its critical role in the innate immune response to Gram-negative bacterial infections including those caused by Escherichia coli, a major mastitis pathogen. Interestingly, E. coli mastitis is particularly severe at calving, a time when metabolic disorders (e.g., ketosis and milk fever) are common in cows due to the energy demands of milk production. It has been hypothesized that these energy demands contribute to a state of immunosuppression and increased risk of mastitis during the period immediately after calving. Based on the findings of this report, further studies are warranted to determine whether TLR-4 involvement in the response to metabolic alterations may impact the ability of the host to mount an immune response to a concurrent infection.

Technical Abstract: Vascular dysfunction is a major complication of metabolic disorders such as diabetes and obesity. The current studies were undertaken to determine if inflammatory responses are activated in the vasculature of mice with diet-induced obesity (DIO), and if so, whether Toll Like Receptor-4 (TLR4), a key mediator of innate immunity, contributes to these responses. Mice lacking TLR4 (TLR4-/-) and wild-type (WT) controls were fed either a low fat (LF) control diet or a diet high in saturated fat (HF) for 8 weeks. In response to HF feeding, both genotypes displayed similar increases of body weight, body fat content, and serum insulin and free fatty acid (FFA) levels compared to mice on a LF diet. In lysates of thoracic aorta from WT mice maintained on a HF diet, IKK-beta activity was increased and this effect was associated with cellular insulin resistance and impaired insulin stimulation of eNOS. In contrast, vascular inflammation and impaired insulin responsiveness were not evident in aortic samples taken from TLR4-/- mice fed the same HF diet, despite comparable increases of body fat mass. Incubation of either aortic explants from WT mice or cultured human microvascular endothelial cells with the saturated FFA, palmitate (100 uM), similarly activated IKK-beta, inhibited insulin signal transduction and blocked insulin-stimulated NO production. Each of these effects was subsequently shown to be TLR4-dependent. These findings identify the TLR4 signaling pathway as a key mediator of the deleterious effects of palmitate on endothelial NO signaling, and are the first to document a key role for TLR4 in the mechanism whereby diet-induced obesity induces vascular inflammation and insulin resistance.