Fan, SiThe prevalence of obesity and its comorbidities, such as insulin resistance and type 2 diabetes are major concerns. Diet-induced obesity and insulin resistance are associated with gut microbiota dysbiosis, specifically, a reduction in diversity and an increase in bacteria taxa linked with host tissue inflammation and extra energy harvest. Prevention strategies focusing on modification of diet and physical activity levels are beneficial, effective, and cost-efficient but difficult to maintain in the long term.Urtica dioica is widely used as a food in several cultures and its extract has been widely studied for intervention against several diseases, but the molecular mechanisms involved are unclear. In addition, most studies have focused on the extract but not the plant as a whole food. Because U. dioica exerts pleiotropic effects in several tissues, we hypothesized that its phytochemicals get into the systemic circulation to reach target tissues, such as abdominal adipose tissue and skeletal muscle but also impact obesity and insulin resistance through pathways involving the gut microbiota and ultimately the gut immune system. The data presented herein was acquired in a mouse model of obesity and insulin resistance. Supplementing the food with whole U. dioica vegetable, attenuated high fat (HF) diet-induced weight gain, fat accumulation, insulin resistance and changed the gut microbiota composition, by increasing diversity and promoting the proliferation of species from the genus Clostridium. This taxon has associated with lower body weight and activation of regulatory T cells (Tregs) in the intestinal immune system. In a second study, we confirmed that U. dioica induced T cells antigenic stimulation, promoted the activation of Tregs and overall protected against HF diet inflammation. Furthermore, besides attenuating HF diet induced fat accumulation, U. dioica promoted the browning or beiging of adipose tissue as evidenced by enhanced gene expression of key markers of this process. Brown or beige adipose tissue displays enhanced fat oxidation. Finally using enteroids derived from small intestinal tissue, we show that in presence of excess nutrients, supplementation with U. dioica reduces the amount fatty acids and glucose absorbed. In conclusion, supplementing a HF diet with U. dioica attenuates fat accumulation and insulin resistance via mechanisms involving the gut microbiota composition and function, the gut immune system and associated inflammation and moderation of amounts of macronutrients absorbed.enDissertationNutrition