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Publication
Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin
resistance and type 2 diabetes.
Authors Perry RJ, Camporez JP, 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
Submitted By Submitted Externally on 11/10/2015
Status Published
Journal Cell
Year 2015
Date Published
Volume : Pages 160 : 745 - 58
PubMed Reference 25662011
Abstract 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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