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


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.
Jelenik
Tomas
T
Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic.
Rossmeisl
Martin
M
Kuda
Ondrej
O
Jilkova
Zuzana Macek
ZM
Medrikova
Dasa
D
Kus
Vladimir
V
Hensler
Michal
M
Janovska
Petra
P
Miksik
Ivan
I
Baranowski
Marcin
M
Gorski
Jan
J
Hébrard
Sophie
S
Jensen
Thomas E
TE
Flachs
Pavel
P
Hawley
Simon
S
Viollet
Benoit
B
Kopecky
Jan
J
D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D018929:Cell Culture Techniques; D018752:Diet, Fat-Restricted; D004041:Dietary Fats / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism* / Q000627:therapeutic use; D005231:Fatty Acids, Unsaturated / Q000378:metabolism* / Q000494:pharmacology; D015309:Glucose Clamp Technique; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006946:Hyperinsulinism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D024821:Metabolic Syndrome / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D021122:Protein Subunits / Q000378:metabolism
D004041:Dietary Fats; D015525:Fatty Acids, Omega-3; D005231:Fatty Acids, Unsaturated; D021122:Protein Subunits; C534978:Prkaa2 protein, mouse; D055372:AMP-Activated Protein Kinases