<p>This study investigates the effects of diet-induced (alimentary) obesity and leptin-resistant obesity on the composition and metabolic activity (phylometabolic profile) of the mouse gut microbiota. C57Bl/6 mice fed a high-fat diet served as a model of alimentary obesity, while db/db mice, genetically deficient in the functional leptin receptor, modeled leptin-resistant obesity. High-throughput sequencing and metabolic reconstruction were used to analyze the gut microbiota in both models. Key findings revealed that both obesity types significantly altered the gut microbiota, but with distinct patterns. Alimentary obesity was associated with increased relative abundance of Actinobacteria, Cyanobacteria, and Verrucomicrobia and decreased Firmicutes, TM7, and Tenericutes. This coincided with a broad reduction in the metabolic pathways, including those involved in nucleotide and carbohydrate metabolism, amino acid and protein synthesis, and the production of key metabolites (acetate, vitamins, fatty acids). Leptin-resistant obesity showed a decreased relative abundance of Actinobacteria, TM7, Tenericutes, Deferribacteres, Cyanobacteria, and Verrucomicrobia. This type of obesity was accompanied by a decrease in the synthesis of vitamins, cofactors and short-chain fatty acids, and increase in amines degradation pathways. These results demonstrated that leptin resistance had a substantial and distinct impact on the gut microbiota, comparable in magnitude to that of a high-fat diet. Both types of obesity impaired the establishment of a healthy gut microbiota, suggesting a complex interplay between diet, genetics, and the gut microbiota in the pathogenesis of obesity.</p>