, Volume 50, Issue 2, pp 355–367 | Cite as

Short-term administration of GW501516 improves inflammatory state in white adipose tissue and liver damage in high-fructose-fed mice through modulation of the renin-angiotensin system

  • D’Angelo C. Magliano
  • Aline Penna-de-Carvalho
  • Manuel Vazquez-Carrera
  • Carlos A. Mandarim-de-Lacerda
  • Marcia B. Aguila
Original Article


High activation of the angiotensin-converting enzyme (ACE)/(angiotensin-II type 1 receptor) AT1r axis is closely linked to pro-inflammatory effects and liver damage. The aim of this study was to evaluate the effects of the short-term administration of GW501516 on pro-inflammatory markers in white adipose tissue (WAT) and hepatic stellate cells (HSCs), lipogenesis and insulin resistance in the liver upon high-fructose diet (HFru)-induced ACE/AT1r axis activation. Three-month-old male C57Bl/6 mice were fed a standard chow diet or a HFru for 8 weeks. Then, the animals were separated randomly into four groups and treated with GW501516 for 3 weeks. Morphological variables, systolic blood pressure, and plasma determinations were analyzed. In the WAT, the ACE/AT1r axis and pro-inflammatory cytokines were assessed, and in the liver, the ACE/AT1r axis, HSCs, fatty acid oxidation, insulin resistance, and AMPK activation were evaluated. The HFru group displayed a high activation of the ACE/AT1r axis in both the WAT and liver; consequently, we detected inflammation and liver damage. Although GW501516 abolished the increased activation of the ACE/AT1r axis in the WAT, no differences were found in the liver. GW501516 blunted the inflammatory state in the WAT and reduced HSC activation in the liver. In addition, GW501516 alleviates damage in the liver by increasing the expression of the genes that regulate beta-oxidation and decreasing the expression of the genes and proteins that are involved in lipogenesis and gluconeogenesis. We conclude that GW501516 may serve as a therapeutic option for the treatment of a highly activated ACE/AT1r axis in WAT and liver.


ACE/AT1r axis GW501516 Hepatic stellate cells AMPK Inflammation 



The authors would like to thank Ms. Michele Soares and Ms.Gezileia Lau for their technical assistance. This research was supported by the Brazilian agencies CNPq (Brazilian Council of Science and Technology,, Grant #302.154/2011-6 to CAMdL, and #306.077/2013-2 to MBA), FAPERJ (Rio de Janeiro Foundation for Research,, Grant #102.944/2011 to CAMdL, and #103.062/2011), and CAPES (Coordination for Perfectionnement of Superior Personal,, scholarship to DCM).

Conflict of interest

The authors have no conflicts of interest to disclose in this research.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • D’Angelo C. Magliano
    • 1
    • 2
    • 3
  • Aline Penna-de-Carvalho
    • 1
  • Manuel Vazquez-Carrera
    • 2
    • 3
  • Carlos A. Mandarim-de-Lacerda
    • 1
  • Marcia B. Aguila
    • 1
  1. 1.Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of BiologyState University of Rio de JaneiroRio de JaneiroBrazil
  2. 2.Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, Institute of Biomedicine of the University of Barcelona (IBUB)University of BarcelonaBarcelonaSpain
  3. 3.Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos IIIMadridSpain

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