Lipids, Inflammatory Pathways, and Insulin Resistance

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DESCRIPTION (provided by applicant): The association of chronic low grade inflammation with obesity and type II diabetes is now well established. Moreover, substantial evidence now suggests a link between elevated inflammatory status and the pathogenesis of insulin resistance. Thus, interventions that decrease or prevent specific inflammatory responses improve insulin sensitivity. Based on their importance to understanding the pathogenesis and treatment of insulin resistance, we are currently concentrating our efforts on the identification of mechanisms that may initiate inflammatory responses in obesity. Our work has concentrated on one of these putative mechanisms, namely hyperlipidemia. We have established that one of the principal inflammatory pathways (IKK/IkappaB/NF-kappaB) is activated by saturated fatty acids in skeletal muscle and in preliminary data we demonstrate that one mechanism of action of fatty acids on the IKK/IkappaB/NF-kappaB (NF-kappaB) pathway is to stimulate toll-like receptor (TLR) activity. This work has established one biochemical link between lipids, inflammatory pathway activity and a proximal mediator of the innate immune response (TLR's). The hypothesis to be tested in the current proposal is simply that TLR's play a role in vivo in initiating and maintaining the inflammatory response and associated insulin resistance in obesity, and that one possible driving force of TLR activation is hyperlipidemia. These experiments will increase our understanding of the role of hyperlipidemia in activation of inflammatory pathways, the role of TLR's in mediating the effects of lipids, and the relationship between elevated inflammatory responses and the pathogenesis of insulin resistance.