ECE2017 Eposter Presentations: Diabetes, Obesity and Metabolism Cardiovascular Endocrinology and Lipid Metabolism (29 abstracts)
The dual FXR/TGR5 agonist INT-767 counteracts nonalcoholic steatohepatitis and visceral adipose tissue dysfunction in a rabbit model of high fat diet-induced metabolic syndrome
Paolo Comeglio 2 , Ilaria Cellai 2 , Sandra Filippi 1 , Annamaria Morelli 5 , Erica Sarchielli 5 , Luciano Adorini 4 , Mario Maggi 2, & Linda Vignozzi 2,
1Interdepartmental Laboratory of Functional and Cellular Pharmacology of Reproduction, Department of Neuroscience, Phychology, Drug Research and Child Care, University of Florence, Florence, Italy; 2Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy; 3I.N.B.B., Rome, Italy; 4Intercept Pharmaceuticals, New York, USA; 5Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
The nuclear Farnesoid X receptor (FXR) and the G protein-coupled bile acid receptor 1 (TGR5) are bile acids receptors that play a key role in energy metabolism. In an animal model of non-genomic metabolic syndrome (MetS), obtained with a high fat diet (HFD), treatment with the dual FXR/TGR5 agonist INT767 reduced visceral adipose tissue (VAT) accumulation, insulin resistance, hypercholesterolemia and nonalcoholic steatohepatitis (NASH). In liver, INT767 reduced the high macrophage M1 (pro-inflammatory)/M2 (anti-inflammatory) ratio observed in MetS. Furthermore, INT767 increased the expression of: IL10 and FOXP3, markers of M2 macrophage and Treg cell, respectively; PPARα, marker of hepatic fatty acid metabolism; VAMP4 and Syntaxin5, markers of lipid droplet formation; IRS1 and STAMP2, markers of insulin signaling while decreased lipogenesis markers. Moreover histomorphological sign of NASH were significantly improved by INT767.
MetS induced insulin resistance, which shows VAT derangements like adipocytes hypertrophy and reducted GLUT4 translocation to membrane. Treatment with INT767 counteract these VAT alterations and induced the expression of brown adipocytes markers. The analysis of preadipocytes (rPADs) obteined from INT767-treated rabbit and HFD rabbit revealed that INT767 improved insulin sensitivity and mitochondrial ultrastructure and dynamic whereas reduced superoxide production. In rPADs, when compared to HFD, INT767 increased the expression of CIDEA and TMEM (brown fat markers); TFAM and NRF1 (mitochondriogenesis markers); SDHB (membrane respisatory chain marker) and MFN2 and FIS1, (mitochondria fusion/fission markers).
To conclude, INT767 significanlty improves NASH and VAT alterations induced by HFD, restoring insulin sensitivity and inducing the differentiation of rPADs to a metabolically healthy phenotype.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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