Why the study?
To evaluate the effect of oral treatment with A-1317, a novel Ang-(1-7) analog combining the substrate and activator of nitric oxide, on liver-glucose metabolism in high-fat diet-induced metabolic syndrome.
Does oral A-1317 improve metabolic and hemodynamic parameters in rats with high-fat diet-induced metabolic syndrome?
Does oral A-1317 improve metabolic and hemodynamic parameters in rats with high-fat diet-induced metabolic syndrome?
The novel Ang-(1-7) analog A-1317 ameliorates metabolic syndrome disorders in rats, likely via MRGD activation of AMPK and increasing pancreatic β cell function.
Answers are grounded in this paper and cite their sources.
A-1317 merits further preclinical testing in metabolic syndrome; leaves open translation to human therapy.
In previous studies we have shown that oral Ang-(1-7) has a beneficial therapeutic effect on cardiometabolic disturbances present in metabolic syndrome (MetS). Based on the fact that Ang-(1-7) acts through release of nitric oxide (NO), a new peptide, A-1317 was engineered adding the amino acid L-Arginine, the NO precursor, to the N-terminal portion of the Ang-(1-7). Therefore, in a single molecule the substrate and the activator of NO are combined. In the present study, we evaluated the effect of A-1317 oral treatment on the liver-glucose metabolism in MetS induced by high fat (HF) diet in rats. Rats were subjected to control (AIN-93M, CT) or HF diets for 15 weeks to induce MetS and treated with A-1317, Ang-(1-7) included into hydroxypropyl-β-cyclodextrin (HPβCD) or empty HPβCD (E), in the last 7 weeks. At the end of 15 weeks, hemodynamic, biometric and biochemical parameters, redox process and qRT-PCR gene expression of NO synthase and RAS components were evaluated in the liver. HF/E rats increased gain body mass, adiposity index, despite the reduction in food intake, increased plasma leptin, total cholesterol, triglycerides, ALT, fasting blood glucose, OGTT and insulin, HOMA-IR and MAP and HR Furthermore, the MetS rats presented increased in liver angiotensinogen, AT1R, ACE mRNA gene expression and concentration of MDA and carbonylated protein. Both, Ang-(1-7) and A-1317, oral treatment in MetS rats reverted most of these alterations. However, A-1317 was more efficient in reducing body mass gain, ALT, AST, total cholesterol, insulin, fasting blood glucose, ameliorating β cell capacity by increasing HOMA-β and QUICKI whereas Ang-(1-7) reduced HOMA-β and QUICKI. In addition, Ang-(1-7) increased Mas and AKT liver mRNA gene expression, while A-1317 increased both Mas and MRGD and AMPK liver mRNA gene expression, suggesting a distinct pathway of action of Ang-(1-7) and A-1317 in MetS rats. Taken together, our data showed that treatment with A-1317 was able to ameliorate MetS disorders and suggest that this effect was mainly via MRGD via activation of AMPK and increasing β cell function.
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Barbosa et al. (2020) studied this question.
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