Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.
Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.
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DOI：
10.1016/j.cell.2015.01.012
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发表时间：
2015-02-12
期刊：
影响因子：
64.5
通讯作者：
Shulman GI
中科院分区：
文献类型：
--
作者：
Perry RJ;Camporez JG;Kursawe R;Titchenell PM;Zhang D;Perry CJ;Jurczak MJ;Abudukadier A;Han MS;Zhang XM;Ruan HB;Yang X;Caprio S;Kaech SM;Sul HS;Birnbaum MJ;Davis RJ;Cline GW;Petersen KF;Shulman GI
胰岛素介导的肝葡萄糖生成抑制（HGP）受损在2型糖尿病（T2 D）的发病机制中起着重要作用，但其发生的分子机制仍不清楚。使用一种新的体内代谢组学方法，我们发现胰岛素抑制HGP的主要机制是通过抑制白色脂肪组织（WAT）中的脂解减少肝脏乙酰辅酶A，导致丙酮酸羧化酶通量减少。这种机制在胰岛素信号转导基因消除的小鼠和大鼠以及缺乏脂肪甘油三酯脂肪酶的小鼠中得到证实。胰岛素抑制肝脏乙酰辅酶A、PC活性和脂解的能力在高脂喂养的大鼠中丧失，这种现象可通过IL-6中和而可逆，并可通过IL-6输注诱导。综上所述，这些数据确定了WAT衍生的肝乙酰辅酶A是胰岛素对HGP的主要调节剂，并将其与肥胖和T2 D相关的炎症诱导的肝胰岛素抵抗联系起来。
Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin’s ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D.
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影响因子：
7.7
作者：
Kursawe R;Eszlinger M;Narayan D;Liu T;Bazuine M;Cali AM;D'Adamo E;Shaw M;Pierpont B;Shulman GI;Cushman SW;Sherman A;Caprio S
通讯作者：
Caprio S
影响因子：
7.7
作者：
Edgerton DS;Ramnanan CJ;Grueter CA;Johnson KM;Lautz M;Neal DW;Williams PE;Cherrington AD
通讯作者：
Cherrington AD
影响因子：
4.1
作者：
CHISHOLM, AB;ALLAN, EH;TITHERADGE, MA
通讯作者：
TITHERADGE, MA
影响因子：
7.7
作者：
Lewis, GF;Zinman, B;Giacca, A
通讯作者：
Giacca, A
DOI：
10.1016/0006-291x(66)90186-0
发表时间：
1966-01-01
影响因子：
3.1
作者：
BARRITT, GJ;KEECH, DB;LING, AM
通讯作者：
LING, AM