title: Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo, Tokyo, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Eguchi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Oishi-Tanaka
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohsugi
authors.forename: Nozomu
authors.initials: N
authors.lastname: Kono
authors.forename: Fusa
authors.initials: F
authors.lastname: Ogata
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yagi
authors.forename: Umeharu
authors.initials: U
authors.lastname: Ohto
authors.forename: Masao
authors.initials: M
authors.lastname: Kimoto
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010169:Palmitic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D018925:Chemokines; D053594:Myeloid Differentiation Factor 88; D010169:Palmitic Acids; D051197:Toll-Like Receptor 4; C007680:ethyl palmitate