AMP-activated Protein Kinase α2 Subunit Is Required for the Preservation of Hepatic Insulin Sensitivity by n-3 Polyunsaturated Fatty Acids

  1. Jan Kopecky1
  1. 1Department of Adipose Tissue Biology and the
  2. 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;
  3. 3Department of Physiology, Medical University of Bialystok, Poland;
  4. 4Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France;
  5. 5INSERM, U1016, Paris, France;
  6. 6Molecular Physiology Group, Copenhagen Muscle Research Centre, Department of Exercise and Sport Sciences, Section of Human Physiology, University of Copenhagen, Copenhagen, Denmark;
  7. 7Division of Molecular Physiology, College of Life Sciences, University of Dundee, Scotland, U.K.
  1. Corresponding author: Jan Kopecky, kopecky{at}biomed.cas.cz.
  1. T.J. and M.R. contributed equally to this study.

Abstract

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.

Footnotes

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  • Received November 20, 2009.
  • Accepted July 26, 2010.

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  1. Diabetes vol. 59 no. 11 2737-2746
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