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.