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

被引：553

作者：

Eguchi, Kosei ^{[1
]}

Manabe, Ichiro ^{[1
,2
]}

Oishi-Tanaka, Yumiko ^{[1
,3
]}

Ohsugi, Mitsuru ^{[4
]}

Kono, Nozomu ^{[5
]}

Ogata, Fusa ^{[1
]}

Yagi, Nobuhiro ^{[6
]}

Ohto, Umeharu ^{[5
]}

Kimoto, Masao ^{[7
]}

Miyake, Kensuke ^{[8
]}

Tobe, Kazuyuki ^{[9
]}

Arai, Hiroyuki ^{[5
]}

Kadowaki, Takashi ^{[2
,3
,4
]}

Nagai, Ryozo ^{[1
,2
,3
,10
]}

机构：

[1] Univ Tokyo, Grad Sch Med, Dept Cardiovasc Med, Bunkyo Ku, Tokyo 1138655, Japan

[2] Univ Tokyo, Grad Sch Med, Global Ctr Educ & Res Chem Biol Dis, Bunkyo Ku, Tokyo 1138655, Japan

[3] Univ Tokyo, Grad Sch Med, Translat Syst Biol & Med Initiat, Bunkyo Ku, Tokyo 1138655, Japan

[4] Univ Tokyo, Grad Sch Med, Dept Metab Dis, Bunkyo Ku, Tokyo 1138655, Japan

[5] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan

[6] Kyowa Hakko Kirin Co Ltd, Med Chem Res Labs, Nagaizumi, Shizuoka 4118731, Japan

[7] Saga Univ, Fac Med, Dept Biomol Sci, Div Immunol, Saga 8498501, Japan

[8] Univ Tokyo, Inst Med Sci, Div Infect Genet, Minato Ku, Tokyo 1088639, Japan

[9] Toyama Univ, Fac Med, Dept Internal Med 1, Toyama 9300194, Japan

[10] Tokyo Univ Hosp, Translat Res Ctr, Bunkyo Ku, Tokyo 1138655, Japan

来源：

CELL METABOLISM | 2012年 / 15卷 / 04期

关键词：

ENDOPLASMIC-RETICULUM STRESS; TYPE-2; DIABETES-MELLITUS; TOLL-LIKE RECEPTOR-4; INSULIN SENSITIVITY; METABOLIC SYNDROME; GLUCOSE-TOLERANCE; PANCREATIC-ISLETS; ADIPOSE-TISSUE; MACROPHAGES; PLASMA;

D O I：

10.1016/j.cmet.2012.01.023

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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 beta cell dysfunction has remained unclear. We report here the saturated FA palmitate induces beta cell dysfunction in vivo by activating inflammatory processes within islets. Through a combination of in vivo and in vitro studies, we show beta 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 beta cell dysfunction. Islet inflammation also plays an essential role in beta cell dysfunction in T2D mouse models. Collectively, these results demonstrate a clear mechanistic link between beta cell dysfunction and inflammation mediated at least in part via the FFA-TLR4/MyD88 pathway.

引用

页码：518 / 533

页数：16

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