Glycyrrhizin ameliorates high fat diet-induced obesity in rats by activating NrF2 pathway

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Aim:Obesity based on insulin resistance is a state of chronic oxidative stress and inflammation that are highly regulated through nuclear factor Erythroid 2-related factor 2 (NrF2) pathway.Materials and methods:70 male Wistar rats were randomized into two models. The prophylactic model was 10 weeks and rats were grouped into: normal group, GL group (received glycyrrhizin 50 mg/kg/day orally along with normal pellet diet), HFD group and HFD+ GL group (received glycyrrhizin along with HFD). The treatment model was 14 weeks and rats were grouped into: normal group, HFD group and HFD + GL group (received glycyrrhizin from the week 10).Key findings:Glycyrrhizin decreased significantly rat weights and insulin resistance, normalized lipid profile and reduced significantly the adipocytes size in adipose tissue and lipid deposition in the liver tissue through histopathologic examination. Furthermore, glycyrrhizin ameliorated obesity-induced oxidative stress which indicated by significant decrease in liver malondialdehyde level (P < 0.001) and increase in the total antioxidant capacity (P < 0.001). Interestingly, molecular mechanism of glycyrrhizin was explored, that included significant reduction of liver gluconeogenic enzymes mRNA expression (P < 0.001), a significant increase of liver insulin receptor, NrF2 and homooxygenase-1 mRNA expressions (P < 0.001) and significant increase and nuclear translocation of NrF2 in liver tissue.Significance:Glycyrrhizin ameliorates HFD-induced obesity in rats that may be attributed to its ability to increase insulin receptor expression and to activate NrF2 and subsequent homooxygenase-1 pathway. Thus, this work represents a safe natural compound (glycyrrhizin) that has a great role either as prophylaxis or treatment for insulin resistance related to obesity.Graphical abstract:The effect of high fat diet (HFD) feeding either for 10 or 14 weeks on rats (A), the proposed mechanism of glycyrrhizin either as prophylaxis or treatment in amelioration of obesity-associated with insulin resistance induced by high fat diet (HFD) feeding in rats (B).G6Pase: glucose-6-phosphatase, HDL-C: high density lipoprotein-cholesterol, HO-1: homooxygenase-1, HOMA IR: homeostatic model assessment of insulin resistance, LDL-C: low density lipoprotein-cholesterol, MDA: malondialdehyde, NrF2: nuclear factor erythroid-derived factor 2-related factor 2, PEPCK: phosphoenolpyruvate carboxykinase, TAC: total antioxidant capacity.

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