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

Jelenik T, Rossmeisl M, Kuda O, Jilkova ZM, Medrikova D, Kus V, Hensler M, Janovska P, Miksik I, Baranowski M, Gorski J, Hébrard S, Jensen TE, Flachs P, Hawley S, Viollet B, Kopecky J - Diabetes (2010)

Bottom Line: We tested a hypothesis whether AMP-activated protein kinase (AMPK) has a role in the beneficial effects of n-3 LC-PUFAs.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic.

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.

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The effect of differential dietary treatment on the regulation of metabolic fluxes in the liver. AICAR-stimulated fatty acid oxidation (A) and insulin-stimulated de novo fatty acid synthesis (B) in cultured hepatocytes isolated from wild-type and AMPKα2−/− mice fed for 9 weeks either a Chow diet, cHF, or cHF+F. For basal nonstimulated rates of lipid metabolism, see supplementary Table 3. The expression of SCD-1 (C) and SREBP-1c (D) genes was quantified in total RNA isolated from the livers of mice subjected to hyperinsulinemic-euglycemic clamp following the differential dietary treatment for 9 weeks. The data are means ± SE (isolated hepatocytes, n = 3 in triplets; hepatic gene expression, n = 5–8). *P < 0.05 versus genotype Chow; †P < 0.05 versus genotype cHF; ‡P < 0.05 versus wild-type on respective diet. A.U., arbitrary units.
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Figure 4: The effect of differential dietary treatment on the regulation of metabolic fluxes in the liver. AICAR-stimulated fatty acid oxidation (A) and insulin-stimulated de novo fatty acid synthesis (B) in cultured hepatocytes isolated from wild-type and AMPKα2−/− mice fed for 9 weeks either a Chow diet, cHF, or cHF+F. For basal nonstimulated rates of lipid metabolism, see supplementary Table 3. The expression of SCD-1 (C) and SREBP-1c (D) genes was quantified in total RNA isolated from the livers of mice subjected to hyperinsulinemic-euglycemic clamp following the differential dietary treatment for 9 weeks. The data are means ± SE (isolated hepatocytes, n = 3 in triplets; hepatic gene expression, n = 5–8). *P < 0.05 versus genotype Chow; †P < 0.05 versus genotype cHF; ‡P < 0.05 versus wild-type on respective diet. A.U., arbitrary units.

Mentions: We sought to determine whether the differential effect of n-3 LC-PUFAs on accumulation of liver triglycerides in wild-type and AMPKα2−/− mice under the clamp conditions could be explained by hepatic lipid metabolism. In cultured hepatocytes isolated from mice following the different dietary treatments, activities of both fatty acid oxidation and de novo fatty acid synthesis were evaluated. The stimulatory effects of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), an AMPK activator, and insulin on fatty acid oxidation and synthesis are shown in Fig. 4A and B, respectively (for corresponding basal metabolic activities, see supplementary Table 3, available in an online appendix). In hepatocytes from both Chow and cHF diet-fed mice, the absence of AMPKα2 was associated with a trend for lower AICAR-stimulated fatty acid oxidation. Although hepatocytes from cHF-fed mice showed reduced stimulatory effect of AICAR irrespective of the genotype, cHF+F feeding normalized this defect in wild-type but not in AMPKα2−/− hepatocytes (Fig. 5A), suggesting AMPK-dependent induction of capacity for fatty acid oxidation by n-3 LC-PUFAs in the liver. The stimulatory effect of insulin on de novo fatty acid synthesis was reduced in hepatocytes from cHF-fed wild-type mice, whereas it was retained in the hepatocytes from cHF-fed AMPKα2−/− mice (Fig. 4B). cHF+F feeding tended to restore the stimulatory effect of insulin only in wild-type hepatocytes (Fig. 4B).


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

Jelenik T, Rossmeisl M, Kuda O, Jilkova ZM, Medrikova D, Kus V, Hensler M, Janovska P, Miksik I, Baranowski M, Gorski J, Hébrard S, Jensen TE, Flachs P, Hawley S, Viollet B, Kopecky J - Diabetes (2010)

The effect of differential dietary treatment on the regulation of metabolic fluxes in the liver. AICAR-stimulated fatty acid oxidation (A) and insulin-stimulated de novo fatty acid synthesis (B) in cultured hepatocytes isolated from wild-type and AMPKα2−/− mice fed for 9 weeks either a Chow diet, cHF, or cHF+F. For basal nonstimulated rates of lipid metabolism, see supplementary Table 3. The expression of SCD-1 (C) and SREBP-1c (D) genes was quantified in total RNA isolated from the livers of mice subjected to hyperinsulinemic-euglycemic clamp following the differential dietary treatment for 9 weeks. The data are means ± SE (isolated hepatocytes, n = 3 in triplets; hepatic gene expression, n = 5–8). *P < 0.05 versus genotype Chow; †P < 0.05 versus genotype cHF; ‡P < 0.05 versus wild-type on respective diet. A.U., arbitrary units.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 4: The effect of differential dietary treatment on the regulation of metabolic fluxes in the liver. AICAR-stimulated fatty acid oxidation (A) and insulin-stimulated de novo fatty acid synthesis (B) in cultured hepatocytes isolated from wild-type and AMPKα2−/− mice fed for 9 weeks either a Chow diet, cHF, or cHF+F. For basal nonstimulated rates of lipid metabolism, see supplementary Table 3. The expression of SCD-1 (C) and SREBP-1c (D) genes was quantified in total RNA isolated from the livers of mice subjected to hyperinsulinemic-euglycemic clamp following the differential dietary treatment for 9 weeks. The data are means ± SE (isolated hepatocytes, n = 3 in triplets; hepatic gene expression, n = 5–8). *P < 0.05 versus genotype Chow; †P < 0.05 versus genotype cHF; ‡P < 0.05 versus wild-type on respective diet. A.U., arbitrary units.
Mentions: We sought to determine whether the differential effect of n-3 LC-PUFAs on accumulation of liver triglycerides in wild-type and AMPKα2−/− mice under the clamp conditions could be explained by hepatic lipid metabolism. In cultured hepatocytes isolated from mice following the different dietary treatments, activities of both fatty acid oxidation and de novo fatty acid synthesis were evaluated. The stimulatory effects of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), an AMPK activator, and insulin on fatty acid oxidation and synthesis are shown in Fig. 4A and B, respectively (for corresponding basal metabolic activities, see supplementary Table 3, available in an online appendix). In hepatocytes from both Chow and cHF diet-fed mice, the absence of AMPKα2 was associated with a trend for lower AICAR-stimulated fatty acid oxidation. Although hepatocytes from cHF-fed mice showed reduced stimulatory effect of AICAR irrespective of the genotype, cHF+F feeding normalized this defect in wild-type but not in AMPKα2−/− hepatocytes (Fig. 5A), suggesting AMPK-dependent induction of capacity for fatty acid oxidation by n-3 LC-PUFAs in the liver. The stimulatory effect of insulin on de novo fatty acid synthesis was reduced in hepatocytes from cHF-fed wild-type mice, whereas it was retained in the hepatocytes from cHF-fed AMPKα2−/− mice (Fig. 4B). cHF+F feeding tended to restore the stimulatory effect of insulin only in wild-type hepatocytes (Fig. 4B).

Bottom Line: We tested a hypothesis whether AMP-activated protein kinase (AMPK) has a role in the beneficial effects of n-3 LC-PUFAs.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Adipose Tissue Biology, Institute of Physiology of the Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic.

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.

Show MeSH
Related in: MedlinePlus