PEX-168 Improves Insulin Resistance, Inflammatory Response and Adipokines in Simple Obese Mice: A Mechanistic Exploration

Abstract Background: Polyethylene glycol losenatide (PEX-168) is a new antidiabetic drug; as such, there are not yet any reports on its weight loss effect. Therefore, this trial was designed to investigate the effect of PEX-168 on simple obese mice.Methods: Thirty healthy male C57BL/6 mice were randomly selected and divided into a control group (NC, n=6) and an obesity model group (n=24). The high-fat diet-induced simple obesity mice were divided into a model control group (HF) and three intervention groups receiving different doses of PEX-168 (low (LD), medium (MD) and high (HD), receiving PEX-168 doses of 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, respectively), with 6 animals in each group. The intervention groups were injected with different doses of PEX-168 intraperitoneally once a week for 12 weeks. Fasting blood glucose (FBG), body weight and food intake were measured from 1 to 12 weeks after PEX-168 injection. The activity of the mice was observed, and serum insulin (INS), C-reactive protein (CRP) chemerin and omentin levels were measured after 12 weeks.Results: Compared with the HF group, the low dose of PEX-168 reduced the body weight of the mice in a short period of time (8 weeks), and the mice in the LD and HD groups showed a significant decrease in body weight (P < 0.05). The low dose of PEX-168 could effectively improve the blood glucose and insulin resistance index (Homa-IR) of the mice (FBG P < 0.05 INS, Homa-IR P < 0.001), but there was no significant difference between different doses (P > 0.05). CRP levels in the HD and LD groups were significantly improved (P < 0.05). The levels of serum chemerin and omentin in the intervention groups were also significantly improved (P < 0.01), but there was no significant difference between the different doses (P > 0.05).Conclusion: PEX-168 significantly reduced the body weight of simple obese mice and prevented the development of diabetes. PEX-168 may regulate the expression of chemerin and omentin mainly through its hypoglycaemic effect, and the weight-reducing effect of PEX-168 is unlikely to be the reason for the changes in both.