Abstract 5676: Free Fatty Acids Induce Dynamic Inflammatory Processes in Pancreatic Islets That Lead to β Cell Dysfunction
Metabolic syndrome is a major risk factor of atherosclerotic cardiovascular disease and previous studies have suggested the pivotal involvement of inflammation in its development. Serum levels of free fatty acids are increased in obese subjects and have been implicated in pathogenesis of both cardiovascular and metabolic diseases. We found that palmitate, the major free fatty acid in blood, when administered to mice markedly exacerbated neointima formation. Interestingly, a continuous infusion of palmitate induced β cell dysfunction. Because neointima formation is an inflammatory process, we addressed if inflammation plays a role in the palmitate-induced islet pathology. In the islets of mice infused with palmitate, the reduction of mRNA of β cell functional markers was accompanied by induction of chemokines including MCP-1 and MIP-1α, and inflammatory cytokines including IL-1β and TNF-α. Flow cytometric analysis showed that palmitate infusion induced rapid accumulation of CD11bhiF4/80+Ly-6C+ M1 macrophages in the islets. When macrophages were depleted in mice, the macrophage accumulation was suppressed and the induction of cytokines and chemokines, and β cell dysfunction induced by palmitate was ameliorated, indicating the causative involvement of macrophages in β cell dysfunction. We further analyzed the signaling mechanisms that controls response to palmitate and found that Toll-like receptor 4 (TLR4) signaling mediates chemokine production in β cells. As expected, palmitate-induced M1 macrophage recruitment and β cell dysfunction were markedly suppressed in TLR4 knockout (KO) and Myd88 KO mice. Finally, to confirm the relevance of these phenomena, the islets of db/db and db/+ mice were analyzed. In the islets of db/db mice, β cell dysfunction was accompanied by induction of cytokines and chemokines, and accumulation of CD11bhiF4/80+Ly-6C+ M1 macrophages were observed. Taken together, results of the present study demonstrate that palmitate induces inflammatory processes in pancreatic islet by recruiting Ly-6C+ inflammatory monocytes/macrophages, which leads to β cell dysfunction. In conclusion, chronic inflammation induced by free fatty acids appears to play important roles in both cardiovascular and metabolic diseases.