| Summary: | Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta‐adrenergic receptor (β‐AR) signaling on the activity of nutrient‐sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high‐fat diet (HFD), a high‐fat/high‐sugar Western diet (WD), a high‐sugar diet with mixed carbohydrates (HCD), or a high‐sucrose diet (HSD). After 6 week on diets, mice were treated with isoproterenol (ISO) and the activity of liver mTOR complex 1 (mTORC1)‐related signaling analyzed by immunoblotting and correlated with tissue triglyceride and glycogen contents. ISO‐stimulated AKT‐ and ERK‐mediated activation of mTORC1 in STD‐fed mice. Consumption of all four high‐calorie diets exacerbated downstream activation of ribosomal protein S6 kinase beta‐1 (S6K1) in response to ISO. S6K1 activity was greater with the fat‐enriched HFD and WD and correlated with the presence of metabolic syndrome and a stronger activation of AKT and ERK1/2 pathways. Fat‐enriched diets also increased triglyceride accumulation and inhibited glycogen mobilization under β‐AR stimulation. In conclusion, crosstalk between β‐AR and insulin signaling may contribute to HFD‐induced hepatic steatosis through ERK1/2‐ and AKT‐mediated hyperactivation of the mTORC1/S6K1 axis. The findings provide further rationale for the development of therapies aimed at targeting augmented β‐AR signaling in the pathogenesis of NAFLD.
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