Saturated Fatty Acid and TLR Signaling Link β Cell Dysfunction and Islet Inflammation

• Published in: Cell metabolism 2012-04, Vol.15 (4), p.518-533
• Main Authors: Eguchi, Kosei, Manabe, Ichiro, Oishi-Tanaka, Yumiko, Ohsugi, Mitsuru, Kono, Nozomu, Ogata, Fusa, Yagi, Nobuhiro, Ohto, Umeharu, Kimoto, Masao, Miyake, Kensuke, Tobe, Kazuyuki, Arai, Hiroyuki, Kadowaki, Takashi, Nagai, Ryozo
• Format: Article
• Language: English
• Subjects: Animals; CD11b Antigen - metabolism; Cell Communication - drug effects; Chemokines - genetics; Chemokines - metabolism; Gene Expression Regulation - drug effects; Inflammation - metabolism; Inflammation - pathology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Mice; Monocytes - drug effects; Monocytes - metabolism; Monocytes - pathology; Myeloid Differentiation Factor 88 - metabolism; Palmitic Acids - administration & dosage; Palmitic Acids - pharmacology; Signal Transduction - drug effects; Toll-Like Receptor 4 - metabolism
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2012.01.023

Consumption of foods high in saturated fatty acids (FAs) as well as elevated levels of circulating free FAs are known to be associated with T2D. Though previous studies showed inflammation is crucially involved in the development of insulin resistance, how inflammation contributes to β cell dysfunction has remained unclear. We report here the saturated FA palmitate induces β cell dysfunction in vivo by activating inflammatory processes within islets. Through a combination of in vivo and in vitro studies, we show β cells respond to palmitate via the TLR4/MyD88 pathway and produce chemokines that recruit CD11b+Ly-6C+ M1-type proinflammatory monocytes/macrophages to the islets. Depletion of M1-type cells protected mice from palmitate-induced β cell dysfunction. Islet inflammation also plays an essential role in β cell dysfunction in T2D mouse models. Collectively, these results demonstrate a clear mechanistic link between β cell dysfunction and inflammation mediated at least in part via the FFA-TLR4/MyD88 pathway. [Display omitted] ► Palmitate induces β cell dysfunction by activating inflammatory processes in islets ► β cells sense palmitate via the TLR4 pathway and recruit M1 macrophages to islets ► M1 macrophages play a pivotal role in palmitate-induced β cell dysfunction ► M1 macrophages and inflammation also play a role in β cell dysfunction in T2D models