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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


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.

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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).

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

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Correspondence to Carlos A. Mandarim-de-Lacerda.

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Magliano, D.C., Penna-de-Carvalho, A., Vazquez-Carrera, M. et al. 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. Endocrine 50, 355–367 (2015).

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  • ACE/AT1r axis
  • GW501516
  • Hepatic stellate cells
  • AMPK
  • Inflammation