Abstract

Background: Pathogenic factors driving obesity-induced fatty liver disease (NAFLD) and insulin resistance are not fully understood. While the mechanisms are unclear, we recognize that high fat diets contribute to obesity, insulin resistance, deleterious ROS production, and fibrogenesis. There is evidence that high fat diets can cause an increased risk of diabetes and consequent cardiovascular disease. The chronic overnutrition from high fat diets is increasingly seen as a risk factor for cardio-metabolic diseases. Previously, we established that pharmacological and herbal medication increase the antioxidant and anti-obesity gene heme oxygenase -1 (HO-1), which reduces inflammatory adipokines and hepatosteatosis. Objective: We examined whether targeting adipocytes to overexpress HO-1 would ameliorate the negative metabolic effects of a prolonged high fat diet (HFD) in mice in hepatocyes as well as adipocytes, to reverse NAFLD and prevent subsequent cardiovascular complications. Methods: Mice were administered lentiviral adiponectin-HO-1 after 20 weeks of a HFD and continued on this diet for 8 more weeks, for a total of 28 weeks of HFD. Mice were treated with HO-1 or a sham virus. Mice were euthanized at 28 weeks. Results: HFD induced adipocyte hypertrophy, increased levels of inflammatory adipokines, and the presence of hepatic lipid droplets and steatosis. The treated mice had less liver lipid droplet accumulation, with normal glucose tolerance and vascular function. These beneficial effects of adipocyte-targeted expression of HO-1 correlated with a reduction in inflammatory adipokines and increased insulin receptor phosphorylation. We have demonstrated that selective increased HO-1 expression in adipose tissue via viral transfection, improved mitochondrial function in both adipose tissue and hepatic tissue in a murine model of high fat diet-induced obesity and NAFLD. Conclusion: This represents a unique therapeutic strategy for treating obesity-associated hepatic steatosis and metabolic syndrome from chronic overnutrition and downstream cardiovascular complications.Background: Pathogenic factors driving obesity-induced fatty liver disease (NAFLD) and insulin resistance are not fully understood. While the mechanisms are unclear, we recognize that high fat diets contribute to obesity, insulin resistance, deleterious ROS production, and fibrogenesis. There is evidence that high fat diets can cause an increased risk of diabetes and consequent cardiovascular disease. The chronic overnutrition from high fat diets is increasingly seen as a risk factor for cardio-metabolic diseases. Previously, we established that pharmacological and herbal medication increase the antioxidant and anti-obesity gene heme oxygenase -1 (HO-1), which reduces inflammatory adipokines and hepatosteatosis. Objective: We examined whether targeting adipocytes to overexpress HO-1 would ameliorate the negative metabolic effects of a prolonged high fat diet (HFD) in mice in hepatocyes as well as adipocytes, to reverse NAFLD and prevent subsequent cardiovascular complications. Methods: Mice were administered lentiviral adiponectin-HO-1 after 20 weeks of a HFD and continued on this diet for 8 more weeks, for a total of 28 weeks of HFD. Mice were treated with HO-1 or a sham virus. Mice were euthanized at 28 weeks. Results: HFD induced adipocyte hypertrophy, increased levels of inflammatory adipokines, and the presence of hepatic lipid droplets and steatosis. The treated mice had less liver lipid droplet accumulation, with normal glucose tolerance and vascular function. These beneficial effects of adipocyte-targeted expression of HO-1 correlated with a reduction in inflammatory adipokines and increased insulin receptor phosphorylation. We have demonstrated that selective increased HO-1 expression in adipose tissue via viral transfection, improved mitochondrial function in both adipose tissue and hepatic tissue in a murine model of high fat diet-induced obesity and NAFLD. Conclusion: This represents a unique therapeutic strategy for treating obesity-associated hepatic steatosis and metabolic syndrome from chronic overnutrition and downstream cardiovascular complications.