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Cell. 2015 Feb 12;160(4):745-758. doi: 10.1016/j.cell.2015.01.012. Epub 2015 Feb 5.

Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.

Author information

1
Howard 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.
2
Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.
3
The Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA.
5
Department of Immunobiology, Yale University, New Haven, CT 06520, USA.
6
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
7
Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA.
8
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA; Department of Comparative Medicine, Yale University, New Haven, CT 06520, USA.
9
Department of Pediatrics, Yale University, New Haven, CT 06520, USA.
10
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
11
Howard Hughes Medical Institute, Yale University, New Haven, CT 06519, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
12
Howard 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: gerald.shulman@yale.edu.

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.

PMID:
25662011
PMCID:
PMC4498261
DOI:
10.1016/j.cell.2015.01.012
[Indexed for MEDLINE]
Free PMC Article

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