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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 …