Macrophage ERK Signaling and Its Application in Modulating Skeletal Muscle Insulin Resistance

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PROJECT SUMMARY/ABSTRACT Insulin resistance precedes and contributes to the development of type 2 diabetes, and it is now believed that chronic inflammation is the source of obesity-induced insulin resistance. Recent studies demonstrate that mouse and human skeletal muscle have an increased macrophage population upon high fat feeding and obesity. However, the molecular mechanisms linking macrophage accumulation in, and insulin resistance of, the skeletal muscle are not known. One possible link is Toll-like receptor 4 (TLR4), a membrane receptor that plays an important role in the innate immune system by activating inflammatory mediators such as extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). The positive regulators of TLR4 signaling after activation, especially the endosomal transport system, remain unclear, and these may be critical in the development of insulin resistance. The hypothesis is that ERK1 and ERK2 positively regulate TLR4-mediated inflammatory responses and that inhibition of ERK signaling will protect against insulin resistance. In the process of pursuing the overall project goal, the following specific aims will be addressed. Aim 1: To characterize the role of ERK1 and ERK2 in regulating TLR4 endocytosis and signaling. Using siRNA, ERK1 and ERK2 isoforms will be knocked down in bone marrow derived macrophages to determine the molecular mechanisms regulating TLR4 endocytosis. Aim 2: To assess the contributions of inhibiting ERK signaling in macrophages to the protection against insulin resistance, and to the regulation of skeletal muscle macrophage infiltration. Insulin clamp studies will be performed to examine whether ERK1 and ERK2 deficiencies in macrophages result in improved insulin sensitivity and protection against high fat diet-induced skeletal muscle inflammation and insulin resistance in a mouse model. The proposed studies in characterizing the phenotype of macrophage ERK1 and ERK2 will contribute to the unraveling and understanding of the specific functions of ERK1 and ERK2 isoforms.