Home » Key Scientific Articles » 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.

Perry RJ1, Camporez JP2, Kursawe R2, Titchenell PM3, Zhang D4, Perry CJ5, Jurczak MJ2, Abudukadier A2, Han MS6, Zhang XM4, Ruan HB7, Yang X8, Caprio S9, Kaech SM5, Sul HS10, Birnbaum MJ3, Davis RJ11, Cline GW2, Petersen KF2, Shulman GI12.

Cell. 2015 Feb 12;160(4):745-58.

1Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA; Department of Internal Medicine, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.

2Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.

3The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

4Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA.

5Department of Immunobiology, Yale University, New Haven, CT 06520, USA.

6Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

7Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA.

8Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA; Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA.

9Department of Pediatrics, Yale University, New Haven, CT 06520, USA.

10Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.

11Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

12Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA; Department of Internal Medicine, Yale University, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA. Electronic address: [email protected]

 

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 lackingadipose 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.

Copyright © 2015 Elsevier Inc. All rights reserved.

Go To PubMed