Abstract
BackgroundThe AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). PPARγ activation is known to modulate metabolic syndrome; however a systems-level investigation looking at the protective effects of PPARγ activation as related to the AROS axis has not been performed.The aim of this work is to simultaneously characterize multiple molecular parameters within the AROS axis, using samples taken from different body fluids and tissues of a rat model of HFD-induced metabolic syndrome, in the presence or absence of a PPARγ agonist, Rosiglitazone (RGZ).MethodsRats were fed with 60% HFD for the first half of the treatment duration (21 days) then continued with either HFD alone or HFD plus RGZ for the second half.ResultsRats receiving HFD alone showed metabolic syndrome manifestations including hypertension, dyslipidemia, increased glucose levels and insulin resistance, as well as abnormal kidney and inflammatory parameters. Systolic blood pressure, plasma triglyceride and glucose levels, plasma creatinine, and albuminuria were significantly improved in the presence of RGZ. The following molecular parameters of the AROS axis were significantly upregulated in our rat model: carboxymethyl lysine (CML) in urine and liver; carboxyethyl lysine (CEL) in urine; advanced glycation end products (AGEs) in plasma; receptor for advanced glycation end products (RAGE) in liver and kidney; advanced oxidation protein products (AOPP) in plasma; and 4-hydroxynonenal (HNE) in plasma, liver, and kidney. Conversely, with RGZ administration, the upregulation of AOPP and AGEs in plasma, CML and CEL in urine, RAGE in liver as well as HNE in plasma and liver was significantly counteracted/prevented.ConclusionsOur data demonstrate (i) the systems-level regulatory landscape of HFD-induced metabolic syndrome involving multiple molecular parameters, including HNE, AGEs and their receptor RAGE, and (ii) attenuation of metabolic syndrome by PPARγ modulation.
Highlights
The advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD)
Many of these diseases are frequently associated with a complex disorder called metabolic syndrome, which is characterized by a group of co-occurring conditions: abdominal obesity, increased blood pressure, increased glucose level and multiple dyslipidaemias [2]; insulin resistance is frequently found to occur in a subset of patients exibiting this syndrome [3]
The results provide a more complete picture of the landscape of the AGE-RAGE-oxidative stress (AROS) axis, and illustrate the potential value of a systems approach in evaluating new drug candidates and the complex molecular mechanisms involved in metabolic syndrome
Summary
The AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). Chronic non-communicable diseases such as diabetes, heart disease and cancer are responsible for 35 million deaths annually [1] Many of these diseases are frequently associated with a complex disorder called metabolic syndrome, which is characterized by a group of co-occurring conditions (though not necessarily all occurring in the same patient): abdominal obesity, increased blood pressure, increased glucose level and multiple dyslipidaemias [2]; insulin resistance is frequently found to occur in a subset of patients exibiting this syndrome [3]. Nonenzymatic protein glycation and lipoxidation have emerged as major candidates for initiating and sustaining this syndrome [4]
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