Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance
- Naoki Kumashiro1,2,
- Sara A. Beddow4,
- Daniel F. Vatner2,
- Sachin K. Majumdar2,
- Jennifer L. Cantley1,2,
- Fitsum Guebre-Egziabher2,
- Ioana Fat2,
- Blas Guigni2,
- Michael J. Jurczak2,
- Andreas L. Birkenfeld2,
- Mario Kahn2,
- Bryce K. Perler2,
- Michelle A. Puchowicz5,
- Vara Prasad Manchem6,
- Sanjay Bhanot6,
- Christopher D. Still7,
- Glenn S. Gerhard7,
- Kitt F. Petersen2,
- Gary W. Cline2,
- Gerald I. Shulman1,2,3 and
- Varman T. Samuel2,4,*
- 1Howard Hughes Medical Institute
- Departments of 2Internal Medicine and
- 3Cellular & Molecular Physiology. Yale University School of Medicine, New Haven, Connecticut, USA.
- 4Veterans Affairs Medical Center, West Haven Connecticut, USA.
- 5Department of Nutrition, Case Western Reserve University, Cleveland, Ohio, USA.
- 6ISIS Pharmaceuticals, Carlsbad, California, USA.
- 7Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania, USA.
- *Corresponding author: Varman T. Samuel,
We measured the mRNA and protein expression of the key gluconeogenic enzymes in human liver biopsies, and found that only hepatic pyruvate carboxylase protein levels related strongly with glycemia. We assessed the role of pyruvate carboxylase in regulating glucose and lipid metabolism in rats through a loss-of-function approach using a specific antisense oligonucleotide (ASO) to decrease expression predominantly in liver and adipose tissue. Pyruvate carboxylase ASO reduced plasma glucose concentrations and the rate of endogenous glucose production in vivo. Interestingly, pyruvate carboxylase ASO also reduced adiposity, plasma lipid concentrations, and hepatic steatosis in high-fat-fed (HFF) rats and improved hepatic insulin sensitivity. Pyruvate carboxylase ASO had similar effects in ZDF rats. Pyruvate carboxylase ASO did not alter de novo fatty acid synthesis, lipolysis, or hepatocyte fatty acid oxidation. In contrast, the lipid phenotype was attributed to a decrease in hepatic and adipose glycerol synthesis, which is important for fatty acid esterification when dietary fat is in excess. Tissue specific inhibition of pyruvate carboxylase is a potential therapeutic approach for nonalcoholic fatty liver disease, hepatic insulin resistance and type 2 diabetes.
- Received September 24, 2012.
- Accepted February 9, 2013.
- © 2013 by the American Diabetes Association.
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