Inhibition by lipid overload

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An increasing body of evidence indicates that dysregulation of AMPK activity and its consequential signaling network may have sustained and deleterious effects at the systemic level that underlie the pathogenesis of metabolic syndrome (Ruderman and Prentki, 2004). A strong correlation between low activation state of AMPK and metabolic disorders associated with insulin resistance, obesity and sedentary activities has been established in a variety of rodent models with aspects of the metabolic syndrome (Kelly et al., 2004; Yu et al., 2004). In addition, feeding mice with a high fat diet causes dysregulation of AMPK, associated with impaired AMPK phosphorylation and protein expression in skeletal muscle, heart, liver, aortic endothelium and hypothalamus (Lee et al., 2005; Lessard et al., 2006; Liu et al., 2006; Martin et al., 2006; Muse et al., 2004; Wang and Unger, 2005; Wilkes et al., 2005). Furthermore, inhibition of AMPK was found to occur in mice fed with a high fat diet rich in palmitate (Wu et al., 2007), raising the possibility that chronic exposure to fatty acids inhibits AMPK activation in a feed-forward effect of lipid overload. It was reported that palmitate inhibited AMPK in endothelial cells via ceramide-dependent PP2A activation (Wu et al., 2007). Interestingly, AMPK inhibition by PP2C upregulation was accounted for decreased AMPK activity in the heart of obese rodents with cardiac lipotoxicity (Wang and Unger, 2005). These data provide new insights into the mechanisms of lipo-regulatory dysfunction, leading to lipid metabolism disorders in obesity.

If decreased AMPK activity contributes to the pathogenesis of obesity, as suggested by dysregulation of AMPK signaling in obese rodent models, one would expect that mice lacking AMPK will be more sensitive to deleterious effects of over-nutrition. Consistent with this hypothesis, whole-body ablation of AMPKa2 activity exacerbates high fat diet-induced obesity, while the glucose disposal rates are similar to those of wild-type mice (Villena et al., 2004). The fact that these mice have similar triglycerides contents in liver and muscle, either on high-fat or normal diets, rules out the lipid accumulation in these tissues as a major determinant of their glucose homeostasis (Villena et al., 2004). More recently, Jorgensen and coworkers investigated whether reduced levels of muscle AMPK promoted lipid accumulation and insulin resistance during high-fat diet (Beck Jorgensen et al., 2009). High-fat feeding increased body mass and adiposity, and impaired insulin and glucose tolerance, however, there was no difference between wild-type and transgenic litter-mates overexpressing an AMPKa2 kinase-dead (KD) in muscle. High-fat feeding decreased insulin-stimulated muscle glucose uptake and Akt-phosphorylation, while increasing muscle triacylglycerol, diacylglycerol and ceramide. These effects, as well as obesity-induced lipid accumulation and insulin resistance were not exacerbated in AMPK KD mice, suggesting that reduced levels of muscle AMPKa2 did not promote insulin resistance in the early phase of obesity-related diabetes. Another study by Fujii and coworkers demonstrated that mice overexpressing a muscle-specific KD AMPKa2 Asp157Ala mutation developed more severe muscle insulin resistance after 30 weeks on high-fat diet (Fujii et al., 2008). However, the observation that the genotype effect occurred 26 weeks late than the first evidence of glucose intolerance suggested that AMPK did not play a primary role in the development of insulin resistance. Thus, while AMPK function is impaired with severe obesity, it does not appear to influence the development of insulin resistance in diet-induced obesity.