The etiopathogenesis of obesity-related chronic kidney disease (CKD) is still scarcely understood. Aim of this study is to shed light on the molecular pathogenesis of obesity-induced CKD by assessing the effect of high fat diet (HF) on molecular pathways leading to organ damage, steatosis, and fibrosis. Six-week-old male C57BL/6N mice were fed HF diet or normal chow for 20-weeks. Kidneys were collected for genomic, proteomic, histological studies and lipid quantification. The main findings were as follows: 1) HF diet activated specific pathways leading to fibrosis and increased fatty acid metabolism; 2) HF diet promoted a metabolic shift of lipid metabolism from peroxisomes to mitochondria; 3) no signs of lipid accumulation and/or fibrosis were observed, histologically; 4) the early signs of kidney damage seemed to be related to changes in membrane protein expression and/or oxidative stress; 5) the proto-oncogene MYC was the top upstream transcriptional regulator of changes occurring in protein expression. These results demonstrated the potential usefulness of specific selected molecules as early marker of injury in HF, while histomorphological changes become visible late in CDK progression. The integration of these data with data from biological fluids could help the identification of biomarkers useful for the clinical practice.