Antioxidant-upregulated mesenchymal stem cells reduce inflammation and improve fatty liver disease in diet-induced obesity

Background: The incidence of obesity and diabetes is increasing rapidly. Optimal management is still elusive. Obesity associated with type 2 diabetes is known to cause adipose tissue inflammation, increase oxidative stress, and cause white fat hyperplasia and mitochondrial dysfunction. In this study, we investigated whether mitochondrial and cytosolic antioxidant-upregulated mesenchymal stem cell (MSC) delivery reduces oxidative stress and subsequently improves glucose tolerance, reduce systemic inflammation, and improves fatty liver disease in diet-induced obese (DIO) mouse models. Methods: Antioxidant genes Sod2 (mitochondrial) and catalase (cytosolic) or null (control) were upregulated in human adipose tissue-derived MSCs using adenoviral constructs. Modified MSCs were then delivered intraperitoneally into mice that were fed a 45% or 60% high-fat diet (HFD), and animals were followed for 4 weeks. Results: Over 4 weeks, body weight remained stable; however, we noted a significant reduction in liver fat content by histological analysis and liver triglyceride assay. Triglyceride assay (p < 0.01) confirmed reduced liver fat accumulation in animals that received either Sod2- or Cat-MSCs. There was a lower plasma level of inflammatory marker TNFα, measured in mice that were fed either 45% or 60% HFD and received Sod2- or Cat-MSCs, indicating reduced systemic inflammation. Ucp1 mRNA was upregulated approximately 100-1000-fold for omental fat and 10-100-fold for pericardial fat compared to the Null-MSC-receiving group. Pcgc1a and Prdm16 mRNA upregulation was also noted particularly for pericardial fat. Glucose tolerance showed a positive improvement trend with a lower area under the curve (AUC) values for both Sod2- and Cat-MSCs groups in comparison to control. For mice fed with 60% HFD and that received Sod2-MSCs, glucose levels were significantly lower than control (*p < 0.05) at a time point of 60 min in the glycemic curve during glucose tolerance test. Conclusion: Reduction of oxidative stress post-antioxidant-upregulated MSC delivery, intraperitoneally, reduces systemic inflammation and fat accumulation in the liver. There is evidence of an increase in browning of white adipose tissue depots with concomitant improvement of glucose tolerance in a weight-independent fashion. Antioxidant-upregulated MSC delivery may be a safe yet effective therapy for obesity and prediabetes and improves related complication such as non-alcoholic fatty liver disease.