Experimental Study On The Anti - Metabolic Syndrome Of CX Series Compounds And Its Mechanism

Metabolic syndrome (MS) is mainly characterized by central obesity, high blood glucose or impaired glucose tolerance, dyslipidemia and hypertension, of which insulin resistance is a common pathophysiological basis. Nonalcoholic fatty liver disease is considered the hepatic manifestation of MS. PTP1B, a key negative regulator of both insulin and leptin signaling pathways, is recognized as a potential molecular targets of insulin sensitizers. This study is intend to screening effective PTP1B inhibitors on metabolic treatment, furthermore, to investigate the effects and the mechanism of compound CX09050 on MS treatment.The DIO mouse model was induced by high-fat-diet in C57BL/6J mice, charactered with insulin resistance, impared glucose tolerance, lipid metablic dysfunction and obesity. Insulin sensitivity was determined by ITT, serum insulin levels, HOMA-IR and GIR value in hyperinsulinemic-euglycemic clamp test. The carbohydrate metabolism was evaluated by fasting blood glucose and GTT. The lipid metabolism was evaluated by body weight, levels of serum TC and TG. Lipid accumulation in liver was estimated by the content of hepatic TG and the histological pathological analysis. The effect on the target PTP1B was assessed by the activity of recombinate human PTP1B and the intracellular PTP1B activity in PTP1B overexpression 293T cells in vitro, and by the hepatic PTP1B expressions in vivo, respectively.The expressions of related proteins in liver were measured by Western blot.The screening results showed that compound CX09050 and CX09098 can ameliorate MS. Compound CX09050 inhibited hPTP1B activity and intracellular PTP1B activity in vitro and significantly down-regulated hepatic PTP1B expression in vivo. CX09050 treatment dose-dependently ameliorated insulin resistance, glycometabolic disorder and dyslipidemia in DIO mice. In addition, hepatic TG content and pathological changes of livers were significantly attenuated after administration with CX09050 in DIO mice. In liver of CX09050 group, phosphorylation of IRβ and AKT were up-regulated, while SREBP-1c, FAS and ACC expressions were significantly decreased, respectively, compared with Model group.These results suggest that compound CX09050 can ameliorate MS by increasing insulin sensitivity and decreasing hepatic lipogenesis, probably through the target PTP1B.