AMP-activated Protein Kinase α2 Subunit Is Required for the Preservation of Hepatic Insulin Sensitivity by n-3 Polyunsaturated Fatty Acids
- Tomas Jelenik1,
- Martin Rossmeisl1,
- Ondrej Kuda1,
- Zuzana Macek Jilkova1,
- Dasa Medrikova1,
- Vladimir Kus1,
- Michal Hensler1,
- Petra Janovska1,
- Ivan Miksik2,
- Marcin Baranowski3,
- Jan Gorski3,
- Sophie Hébrard4,5,
- Thomas E. Jensen6,
- Pavel Flachs1,
- Simon Hawley7,
- Benoit Viollet4,5 and
- Jan Kopecky1
- 1Department of Adipose Tissue Biology and the
- 2Department of Analysis of Biologically Important Compounds, Institute of Physiology of the Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic;
- 3Department of Physiology, Medical University of Bialystok, Poland;
- 4Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France;
- 5INSERM, U1016, Paris, France;
- 6Molecular Physiology Group, Copenhagen Muscle Research Centre, Department of Exercise and Sport Sciences, Section of Human Physiology, University of Copenhagen, Copenhagen, Denmark;
- 7Division of Molecular Physiology, College of Life Sciences, University of Dundee, Scotland, U.K.
- Corresponding author: Jan Kopecky, .
T.J. and M.R. contributed equally to this study.
OBJECTIVE The induction of obesity, dyslipidemia, and insulin resistance by high-fat diet in rodents can be prevented by n-3 long-chain polyunsaturated fatty acids (LC-PUFAs). We tested a hypothesis whether AMP-activated protein kinase (AMPK) has a role in the beneficial effects of n-3 LC-PUFAs.
RESEARCH DESIGN AND METHODS Mice with a whole-body deletion of the α2 catalytic subunit of AMPK (AMPKα2−/−) and their wild-type littermates were fed on either a low-fat chow, or a corn oil-based high-fat diet (cHF), or a cHF diet with 15% lipids replaced by n-3 LC-PUFA concentrate (cHF+F).
RESULTS Feeding a cHF diet induced obesity, dyslipidemia, hepatic steatosis, and whole-body insulin resistance in mice of both genotypes. Although cHF+F feeding increased hepatic AMPKα2 activity, the body weight gain, dyslipidemia, and the accumulation of hepatic triglycerides were prevented by the cHF+F diet to a similar degree in both AMPKα2−/− and wild-type mice in ad libitum-fed state. However, preservation of hepatic insulin sensitivity by n-3 LC-PUFAs required functional AMPKα2 and correlated with the induction of adiponectin and reduction in liver diacylglycerol content. Under hyperinsulinemic-euglycemic conditions, AMPKα2 was essential for preserving low levels of both hepatic and plasma triglycerides, as well as plasma free fatty acids, in response to the n-3 LC-PUFA treatment.
CONCLUSIONS Our results show that n-3 LC-PUFAs prevent hepatic insulin resistance in an AMPKα2-dependent manner and support the role of adiponectin and hepatic diacylglycerols in the regulation of insulin sensitivity. AMPKα2 is also essential for hypolipidemic and antisteatotic effects of n-3 LC-PUFA under insulin-stimulated conditions.
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- Received November 20, 2009.
- Accepted July 26, 2010.
- © 2010 by the American Diabetes Association.
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