Lynda Bourebaba1,2, Katarzyna Kornicka-Garbowska1,2, Mohamad Al Naem3, Michael Röcken3, Jacek Łyczko4, Krzysztof Marycz5,6,7. 1. Department of Experimental Biology, Wrocław University of Environmental and Life Sciences, Norwida 27B Street, A7 Building, 50-375, Wrocław, Poland. 2. International Institute of Translational Medicine, Malin, Jesionowa 11, 55-114, Wisznia Mała, Poland. 3. Faculty of Veterinary Medicine, Equine Clinic-Equine Surgery, Justus-Liebig-University, 35392, Giessen, Germany. 4. Department of Chemistry, Faculty of Biotechnology and Food Science, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375, Wrocław, Poland. 5. Department of Experimental Biology, Wrocław University of Environmental and Life Sciences, Norwida 27B Street, A7 Building, 50-375, Wrocław, Poland. krzysztofmarycz@interia.pl. 6. International Institute of Translational Medicine, Malin, Jesionowa 11, 55-114, Wisznia Mała, Poland. krzysztofmarycz@interia.pl. 7. Faculty of Veterinary Medicine, Equine Clinic-Equine Surgery, Justus-Liebig-University, 35392, Giessen, Germany. krzysztofmarycz@interia.pl.
Abstract
BACKGROUND: Protein tyrosine phosphatase 1B (PTP1B) is one of the major negative regulators of leptin and insulin signaling, and has been strongly implicated in insulin resistance development in the course of obesity and metabolic syndrome conditions; however, its exact role in controlling adipose tissue biogenesis is still poorly understood. OBJECTIVES: This investigation aimed to elucidate whether selective inhibition of PTP1B using MSI-1436 compound may improve and restore the defective adipogenicity of ASCs isolated from EMS-affected horses. METHODS: Equine ASC EMS cells were cultured under adipogenic conditions in the presence of PTP1B inhibitor and were subsequently tested for expression of the main adipogenic-related genes using RT-qPCR, changes in free fatty acid profiles by means of GC-MS technique, and for mitochondrial dynamics improvement through the analysis of mitochondrial transmembrane potential and oxidative stress. RESULTS: Selective inhibition of PTP1B in equine ASC EMS cells improved substantially adipogenic differentiation by promoting cellular proliferation and normalizing expression of C/EBPalpha, PPARγ, and Adipoq markers that are critical for proper adipogenesis. Levels of secreted adiponectin and PPARγ were also shown to be increased in MSI-1436-conditioned cells, while total leptin levels markedly dropped under the same conditions. Moreover, MSI-1436 treatment enabled the regulation of metabolic-related transcripts that are crosslink to adipogenesis, namely Akt1, Akt2, and SHBG. The obtained results demonstrated also an obvious reduction in intracellular accumulated ROS and NO, as well as mitigated ER stress through the downregulation of Chop, Perk, Atf6, Ire1, and Xbp1 transcripts upon PTP1B inhibition. Furthermore, general fluctuations in FFA composition of all differentiated groups have been highlighted, where palmitic acid, palmitoleic acid, stearic acid, and linolelaidic acid that are known to be associated with the development of metabolic disorders were found to be normalized upon PTP1B inhibition during adipogenic differentiation. CONCLUSION: The presented data provides the evidence that the use of PTP1B inhibitor may be successful in controlling and enhancing adipogenic differentiation of impaired equine ASCs affected by metabolic syndrome, and thus offers new insights for the management of obesity through the regulation of adipose tissue dynamics.
BACKGROUND:Protein tyrosine phosphatase 1B (PTP1B) is one of the major negative regulators of leptin andinsulin signaling, and has been strongly implicated in insulin resistance development in the course of obesity andmetabolic syndrome conditions; however, its exact role in controlling adipose tissue biogenesis is still poorly understood. OBJECTIVES: This investigation aimed to elucidate whether selective inhibition of PTP1B using MSI-1436 compound may improve and restore the defective adipogenicity of ASCs isolated from EMS-affected horses. METHODS:Equine ASC EMS cells were cultured under adipogenic conditions in the presence of PTP1B inhibitor and were subsequently tested for expression of the main adipogenic-related genes using RT-qPCR, changes in free fatty acid profiles by means of GC-MS technique, and for mitochondrial dynamics improvement through the analysis of mitochondrial transmembrane potential and oxidative stress. RESULTS: Selective inhibition of PTP1B in equine ASC EMS cells improved substantially adipogenic differentiation by promoting cellular proliferation and normalizing expression of C/EBPalpha, PPARγ, andAdipoq markers that are critical for proper adipogenesis. Levels of secreted adiponectin andPPARγ were also shown to be increased in MSI-1436-conditioned cells, while total leptin levels markedly dropped under the same conditions. Moreover, MSI-1436 treatment enabled the regulation of metabolic-related transcripts that are crosslink to adipogenesis, namely Akt1, Akt2, andSHBG. The obtained results demonstrated also an obvious reduction in intracellular accumulated ROS and NO, as well as mitigated ER stress through the downregulation of Chop, Perk, Atf6, Ire1, andXbp1 transcripts upon PTP1B inhibition. Furthermore, general fluctuations in FFA composition of all differentiated groups have been highlighted, where palmitic acid, palmitoleic acid, stearic acid, andlinolelaidic acid that are known to be associated with the development of metabolic disorders were found to be normalized upon PTP1B inhibition during adipogenic differentiation. CONCLUSION: The presented data provides the evidence that the use of PTP1B inhibitor may be successful in controlling and enhancing adipogenic differentiation of impaired equine ASCs affected by metabolic syndrome, and thus offers new insights for the management of obesity through the regulation of adipose tissue dynamics.
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