AMP-activated protein kinase α2 subunit is required for the preservation of hepatic insulin sensitivity by n-3 polyunsaturated fatty acids

Diabetes. 2010 Nov;59(11):2737-46. doi: 10.2337/db09-1716. Epub 2010 Aug 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / deficiency
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Culture Techniques
  • Diet, Fat-Restricted
  • Dietary Fats / pharmacology
  • Fatty Acids, Omega-3 / metabolism*
  • Fatty Acids, Omega-3 / therapeutic use
  • Fatty Acids, Unsaturated / metabolism*
  • Fatty Acids, Unsaturated / pharmacology
  • Glucose Clamp Technique
  • Hepatocytes / cytology
  • Hepatocytes / physiology
  • Hyperinsulinism
  • Insulin Resistance
  • Liver / drug effects
  • Liver / enzymology
  • Liver / physiology*
  • Metabolic Syndrome / prevention & control
  • Mice
  • Mice, Knockout
  • Protein Subunits / metabolism

Substances

  • Dietary Fats
  • Fatty Acids, Omega-3
  • Fatty Acids, Unsaturated
  • Protein Subunits
  • AMPK alpha2 subunit, mouse
  • AMP-Activated Protein Kinases