Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice
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 interactio...
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doaj-7e7de2d57ad448a699f5a1dcbd5777e72021-07-13T09:52:28ZengWileyPhysiological Reports2051-817X2021-07-01913n/an/a10.14814/phy2.14958Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male miceSadia Ashraf0Nadia Ashraf1Gizem Yilmaz2Romain Harmancey3Department of Physiology and Biophysics University of Mississippi Medical Center Jackson MS USAJinnah Hospital Lahore Punjab PakistanDepartment of Physiology and Biophysics University of Mississippi Medical Center Jackson MS USADepartment of Physiology and Biophysics University of Mississippi Medical Center Jackson MS USAAbstract 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.https://doi.org/10.14814/phy2.14958fatty liverglycogenhigh‐fat dietinsulinsympathetic nervous system |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sadia Ashraf Nadia Ashraf Gizem Yilmaz Romain Harmancey |
spellingShingle |
Sadia Ashraf Nadia Ashraf Gizem Yilmaz Romain Harmancey Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice Physiological Reports fatty liver glycogen high‐fat diet insulin sympathetic nervous system |
author_facet |
Sadia Ashraf Nadia Ashraf Gizem Yilmaz Romain Harmancey |
author_sort |
Sadia Ashraf |
title |
Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice |
title_short |
Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice |
title_full |
Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice |
title_fullStr |
Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice |
title_full_unstemmed |
Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice |
title_sort |
crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice |
publisher |
Wiley |
series |
Physiological Reports |
issn |
2051-817X |
publishDate |
2021-07-01 |
description |
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. |
topic |
fatty liver glycogen high‐fat diet insulin sympathetic nervous system |
url |
https://doi.org/10.14814/phy2.14958 |
work_keys_str_mv |
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