Anti-obesity effect of combined treatment of hyperforin and amlexanox on ob/ob mice / 中华内分泌代谢杂志

ABSTRACT

Objective:To investigate the effect of combined treatment of hyperforin(HPF) and amlexanox(AM) on obesity and metabolic disorders.Methods:ob/ob mice were used as an obese mice model and treated with HPF alone(2.5 mg/kg intraperitoneal injection) or combined with AM(50 mg/kg, gavage administration) for 4 weeks. Their body weight and food intake were monitored, glucose tolerance test and insulin tolerance test were performed, serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels were detected. Nuclear magnetic resonance was used to detect the body composition and metabolic cage was used to detect the energy consumption. After sampling, HE staining was used to observed the pathological change of fat and liver tissues, Western blotting and enzyme-linked immunosorbent assay(ELISA) were used to detect the cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA) signaling pathway.Results:Compared to the vehicle-treated mice(54.07 g), HPF-treated mice showed attenuated body weight gain(51.33 g, P=0.042) and reduced total fat mass( P=0.011); while administration of HPF in combination with AM(HPF/AM) further reduced the body weight(47.61 g, P=0.041). HE staining analysis showed that HPF alone or HPF/AM treatment both decreased the diameters of adipocytes and infiltration of white fat( P=0.014, P=0.032) in brown adipose tissues, which resulted in a trend of browning. However, HPF/AM-treatment didn′t further diminish adipocytes or reduce lipid accumulation in brown adipose tissues compared to HPF-treated mice. In addition, the basal oxygen consumption rate(VO 2, P<0.001) and(VCO 2, P=0.002) of HPF-treated mice were mainly elevated in the light phase relative to that of control mice; while HPF/AM-treatment further promote the energy consumption both in the dark phase and light phase. Notably, cAMP-PKA signaling pathway was obviously activated under HPF/AM-treatment in inguinal white adipose tissue. Moreover, HPF/AM-treatment showed beneficial effects on glucose metabolism and fatty liver, as indicated by improved insulin resistance, reduced liver steatosis( P=0.049) and the serum ALT levels( P=0.008). Conclusion:Combined administration of HPF and AM is an effective strategy in the treatment of obesity, improvement of metabolic disorders and alleviation of catecholamine resistance.