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

Abstract

OBJECTIVEThe 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 METHODSMice 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).RESULTSFeeding 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.CONCLUSIONSOur 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.

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

“…Ex vivo biochemical analysis FA oxidation was measured using [1-14 C]palmitate in fragments of epididymal fat or gastrocnemius muscle or whole soleus muscle [28], in isolated adipocytes [29], and in hepatocytes isolated from mice following the in vivo treatment [30]. The rate of FA synthesis in epididymal fat was measured by incorporation of 3 H 2 O into saponifiable FAs [9].…”

Augmenting energy expenditure by mitochondrial uncoupling: a role of AMP-activated protein kinase

“…Importantly, lipid catabolism in WAT was always up-regulated, and in situ lipogenesis in WAT was suppressed (Orci et al 2004;Ribet et al 2010;Flachs et al 2005;Tiraby et al 2003;Wilson-Fritch et al 2004), suggesting activation of AMPK Genes Nutr (2012) 7:369-386 381 in response to decreased energy status in WAT. Indeed, when studied under the conditions of the above treatments, AMPK in WAT and other tissues was found to be activated (Jelenik et al 2010;Kopecky et al 2009;Orci et al 2004;Ye et al 2006). Concerning the mechanism of energy expenditure induced by the treatments, mitochondrial uncoupling mediated by UCP1 in WAT adipocytes (Orci et al 2004;Tiraby et al 2003;Petrovic et al 2010;Collins et al 1997;Guerra et al 1998;Himms-Hagen et al 2000) could be involved in most of the cases.…”

“…For example, leptin activates AMPK in adipose tissue, SM, and liver but inhibits it in hypothalamus (Lim et al 2010), while adiponectin and anti-diabetic drugs primarily activate the AMPK in the peripheral tissues. Furthermore, there is a number of natural food components believed to exert beneficial effects on health in association with activation of AMPK like plant polyphenols (Um et al 2010) or n-3 long-chain polyunsaturated fatty acids (n-3 PUFA) (Jelenik et al 2010;Kopecky et al 2009). The role of AMPK in energy metabolism has been most intensively studied in SM, heart, adipose tissue, liver, beta cells, and hypothalamus, that is, tissues that are highly sensitive to changes in energy balance and also actively involved in its regulation.…”

“…Thus, the role of AMPK in the control of hepatic glucose metabolism by thiazolidinediones (TZDs), and also by adiponectin, an insulin-sensitizing adipokine (Zhang et al 2009;Yamauchi et al 2002), should be reconsidered. Functional adiponectin-AMPK regulatory pathway is required for the beneficial effects of both TZDs (Kubota et al 2006) and n-3 PUFA (Jelenik et al 2010) on hepatic glucose metabolism and its sensitivity to insulin.…”

“…Concerning the induction of energy expenditure in WAT, several physiologically relevant treatments in mice have been demonstrated to induce a phenotype similar to that of aP2-Ucp1 mice for review). Thus, treatment using leptin (Orci et al 2004), PPARa agonists (Ribet et al 2010), adrenoreceptor agonists and lipolytic agents (Granneman et al 2003;Yehuda-Shnaidman et al 2010), dietary n-3 polyunsaturated fatty acids (Jelenik et al 2010;Kopecky et al 2009;Flachs et al 2005), and thiazolidinediones acting as specific agonists of PPARc [TZD; (Tiraby et al 2003;Wilson-Fritch et al 2004;Petrovic et al 2010)] resulted in reduced adiposity and metabolic disturbances related to obesity, observed mostly under the conditions of high-fat feeding in obesity-prone C57BL/6 mice. Importantly, lipid catabolism in WAT was always up-regulated, and in situ lipogenesis in WAT was suppressed (Orci et al 2004;Ribet et al 2010;Flachs et al 2005;Tiraby et al 2003;Wilson-Fritch et al 2004), suggesting activation of AMPK Genes Nutr (2012) 7:369-386 381 in response to decreased energy status in WAT.…”