Hepatic Acetyl CoA Links Adipose Tissue Inflammation to Hepatic Insulin Resistance and Type 2 Diabetes

被引：552

作者：

Perry, Rachel J. ^{[1
,2
,3
]}

Camporez, Joao-Paulo G. ^{[2
]}

Kursawe, Romy ^{[2
]}

Titchenell, Paul M. ^{[4
]}

Zhang, Dongyan ^{[1
]}

Perry, Curtis J. ^{[5
]}

Jurczak, Michael J. ^{[2
]}

Abudukadier, Abulizi ^{[2
]}

Han, Myoung Sook ^{[6
]}

Zhang, Xian-Man ^{[1
]}

Ruan, Hai-Bin

Yang, Xiaoyong ^{[3
,7
]}

Caprio, Sonia ^{[8
]}

Kaech, Susan M. ^{[5
]}

Sul, Hei Sook ^{[9
]}

Birnbaum, Morris J. ^{[4
]}

Davis, Roger J. ^{[1
,6
]}

Cline, Gary W. ^{[2
]}

Petersen, Kitt Falk ^{[2
]}

Shulman, Gerald I. ^{[1
,2
,3
]}

机构：

[1] Yale Univ, Howard Hughes Med Inst, New Haven, CT 06519 USA

[2] Yale Univ, Dept Internal Med, New Haven, CT 06519 USA

[3] Yale Univ, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA

[4] Univ Penn, Perelman Sch Med, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA

[5] Yale Univ, Dept Immunobiol, New Haven, CT 06520 USA

[6] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA

[7] Yale Univ, Dept Comparat Med, New Haven, CT 06520 USA

[8] Yale Univ, Dept Pediat, New Haven, CT 06520 USA

[9] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Berkeley, CA 94720 USA

来源：

CELL | 2015年 / 160卷 / 04期

关键词：

NECROSIS-FACTOR-ALPHA; FATTY LIVER-DISEASE; PYRUVATE-CARBOXYLASE; GLUCOSE-HOMEOSTASIS; SIGNAL TRANSDUCER; LIPID DROPLETS; KINASE JAK1; INTERLEUKIN-6; ASSOCIATION; GLUCONEOGENESIS;

D O I：

10.1016/j.cell.2015.01.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：745 / 758

页数：14

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