ERK1 and ERK2 activation modulates diet-induced obesity in mice.

Obesity is a worldwide problem, and dietary lipids play an important role in its pathogenesis. Recently, Erk1 knock-out (ERK1) mice have been shown to exhibit low preference for dietary fatty acids. Hence, we maintained Erk1 mice on a high-fat diet (HFD) to assess the implication of this mitogen-activated protein (MAP) kinase in obesity. The Erk1 mice, fed the HFD, were more obese than wild-type (WT) animals, fed the same diet. Erk1 obese mice gained more fat and liver mass than WT obese animals. No difference was observed in daily food and energy intake in HFD-fed both group of animals. However, feed efficiency was higher in Erk1 than WT animals. Blood cholesterol, triglyceride and insulin concentrations were higher in Erk1 obese mice compared to WT obese animals. Accordingly, homeostatic model assessment of insulin resistance (HOMA-IR) value was higher in Erk1 obese mice compared to WT obese animals. Interestingly, only Erk1 obese mice, but not WT-obese animals, exhibited high degree of phosphorylation of liver MEK, the upstream regulator of ERK1/2. This phenomenon was associated with high liver ERK2 phosphorylation in Erk1 obese mice which also had high liver acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) mRNA expression, suggesting high lipogenesis in these animals. The Erk1 obese mice also had low PPAR-α and CPT1β mRNA, indicating low fatty acid oxidation. Our observations suggest that ERK1 and ERK2 might play key roles in the regulation of obesity.