Mesenchymal Stromal Cells (Mscs) Upregulated With Both Mitochondrial And Cytosolic Antioxidants Improve Fatty Liver Disease In Diet-Induced Obesity (Dio) Mouse Model

Introduction: Elevated oxidative stress by reactive oxygen species and mitochondrial dysfunction have been implicated in diabetes and obesity leading to insulin resistance (IR). Based on our previous study, we investigated to see the effect of two anti-oxidants (one mitochondrial, SOD2 and another one cytosolic, catalase) upregulated together in MSCs and delivered intra peritoneally (IP) in DIO mouse model. Methods: C57BL/6J male mice (4-6weeks old) were obtained from the Jackson Lab. Obesity, glucose intolerance, and insulin resistance were induced by feeding the mice a high-fat diet (HFD) for 13 weeks. Mouse adipose-derived MSCs and adenovirus constructs containing GFP (Null, SOD2 and Catalase), were purchased Commercially. Glucose tolerance test (GTT), liver and fat depots H\u0026 E staining were performed and liver triglycerides (L-TG) were quantified. Results: A significant reduction in L-TG levels were observed in the mice that received Catalase+SOD2-MSCs (2-fold) compared to Null-MSC, which was less than noted either with catalase or SOD2-MSCs alone. This is consistent with the findings of the corresponding liver fat histology. The systemic inflammatory maker plasma TNF-α levels in mice injected with the combination antioxidants showed 1.5 fold decrease compared to Null-MSC though SOD2-MSCs or catalase-MSCs almost demonstrated a decrease compared to Null-MSC. GTT showed an improvement with combination therapy with total area under the curve (AUC) value less than other groups. Discussion: Our results indicate that MSCs with upregulated both Catalase and SOD2 anti-oxidants were more effective in reducing systemic inflammation (plasma TNF-α) and liver triglyceride content in DIO mice. MSC mediated delivery of combination of antioxidants, intra-peritoneally is safe and can be used as an efficient tool for treating obesity, prediabetes and NAFLD. Disclosure S. Nandula: None. N. Kundu: None. S. Sen: None.