%0 Journal Article %J Clin Sci (Lond) %D 2012 %T TNF-related apoptosis-inducing ligand significantly attenuates metabolic abnormalities in high-fat-fed mice reducing adiposity and systemic inflammation. %A Bernardi, Stella %A Zauli, Giorgio %A Tikellis, Christos %A Candido, Riccardo %A Fabris, Bruno %A Secchiero, Paola %A Cooper, Mark E %A Thomas, Merlin C %K Adiposity %K Animals %K Apoptosis %K Calorimetry %K Cytokines %K Dietary Fats %K Energy Intake %K Glucose Tolerance Test %K Hyperglycemia %K Hyperinsulinism %K Inflammation %K Inflammation Mediators %K Male %K Mice %K Mice, Inbred C57BL %K Oxidation-Reduction %K Palmitic Acid %K Real-Time Polymerase Chain Reaction %K TNF-Related Apoptosis-Inducing Ligand %X

TRAIL [TNF (tumour necrosis factor)-related apoptosis-inducing ligand] has recently been shown to ameliorate the natural history of DM (diabetes mellitus). It has not been determined yet whether systemic TRAIL delivery would prevent the metabolic abnormalities due to an HFD [HF (high-fat) diet]. For this purpose, 27 male C57bl6 mice aged 8 weeks were randomly fed on a standard diet, HFD or HFD+TRAIL for 12 weeks. TRAIL was delivered weekly by intraperitoneal injection. Body composition was evaluated; indirect calorimetry studies, GTT (glucose tolerance test) and ITT (insulin tolerance test) were performed. Pro-inflammatory cytokines, together with adipose tissue gene expression and apoptosis, were measured. TRAIL treatment reduced significantly the increased adiposity associated with an HFD. Moreover, it reduced significantly hyperglycaemia and hyperinsulinaemia during a GTT and it improved significantly the peripheral response to insulin. TRAIL reversed the changes in substrate utilization induced by the HFD and ameliorated skeletal muscle non-esterified fatty acids oxidation rate. This was associated with a significant reduction of pro-inflammatory cytokines together with a modulation of adipose tissue gene expression and apoptosis. These findings shed light on the possible anti-adipogenic and anti-inflammatory effects of TRAIL and open new therapeutic possibilities against obesity, systemic inflammation and T2DM (Type 2 DM).

%B Clin Sci (Lond) %V 123 %P 547-55 %8 2012 Nov %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/22616837?dopt=Abstract %R 10.1042/CS20120176 %0 Journal Article %J Atherosclerosis %D 2011 %T Osteoprotegerin promotes vascular fibrosis via a TGF-β1 autocrine loop. %A Toffoli, Barbara %A Pickering, Raelene J %A Tsorotes, Despina %A Wang, Bo %A Bernardi, Stella %A Kantharidis, Phillip %A Fabris, Bruno %A Zauli, Giorgio %A Secchiero, Paola %A Thomas, Merlin C %K Animals %K Apolipoproteins E %K Cell Proliferation %K Collagen %K Fibronectins %K Fibrosis %K Gene Expression Regulation %K Humans %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Muscle, Smooth, Vascular %K Myocytes, Smooth Muscle %K Osteoprotegerin %K Platelet-Derived Growth Factor %K Transforming Growth Factor beta1 %X

BACKGROUND: This study was designed to evaluate the potential role of osteoprotegerin (OPG) in arterial fibrosis.

METHODS: Aortic samples were analyzed after in vivo treatment of ApoE(-/-) mice with recombinant human OPG. Mouse vascular smooth muscle cells (VSMC) were exposed in vitro to recombinant OPG and analyzed for markers of inflammation and fibrosis, such as fibronectin, collagen I, III, IV and transforming growth factor-β1 (TGF-β1). Conversely, the potential modulation of endogenous OPG expression and release by VSMC was analyzed in response to different pro-atherosclerotic cytokines, TGF-β1, platelet derived growth factor (PDGF) and angiogensin II (Ang II).

RESULTS: In vivo treatment with human OPG induced signs of fibrosis and up-regulated the arterial expression of TGF-β1. Consistently, in vitro treatment of VSMC with human OPG induced the expression of fibronectin, collagen type I, III, IV, metalloprotein-2 (MMP-2) and MMP-9, as well as of TGF-β1. On the other hand, exposure to recombinant TGF-β1 promoted the expression/release of endogenous OPG and mediated the increase of OPG release induced by PDGF and Ang II in VSMC.

CONCLUSIONS: Taken together, these data support a pathogenic role for OPG in the development and progression of atherosclerotic lesions and suggest the existence of a vicious circle between TGF-β1 and OPG.

%B Atherosclerosis %V 218 %P 61-8 %8 2011 Sep %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/21679949?dopt=Abstract %R 10.1016/j.atherosclerosis.2011.05.019