Identifying metabolite signatures associated with obesity and related diseases might represent a valuable preventive and therapeutic tool to predict subjects at risk, establish an accurate prognosis, and monitor treatment success. The current cross-sectional study is aimed to evaluate the metabolite profile of diet-induced obesity in a porcine model of leptin resistance. Six Iberian female pigs prone to develop obesity (OB) were ad libitum fed a fat-enriched diet (HFD) for 82 days. Five lean Iberian sows (CON) in a maintenance diet served as controls. At the end of the dietary treatments, all animals were sacrificed, and plasma, liver, and muscle samples were immediately collected for nuclear magnetic resonance analysis. In plasma, signals corresponding to betaine, glycerophosphocholine/phosphocholine, glycine, and glutamate were decreased; and the valine signal was increased in OB sows compared to controls. Similarly, the betaine signal was decreased in the liver. No differences were detected in muscle. The observed metabolite changes suggest alterations in branched chain amino-acid metabolism and the methionine-homocysteine cycle, which have been previously associated with obesity-related diseases and type 2 diabetes in human observational studies. The current study supports the utilization of the leptin resistant Iberian pig for further interventional research in the field.