Body weight and food intake
In the present study, low doses of PEX-168 inhibited the progression of obesity in the short term, and medium to high concentrations of PEX-168 inhibited the development of obesity in the long term. The corresponding changes in food intake and body weight also demonstrated that the weight-reducing effect of PEX-168, like other GLP-1 analogues, was mainly through inhibition of intake, which is also consistent with animal experiments with liraglutide. However, the decrease in food intake was unstable during the intervention and was gradually normalized by the mice as the intervention progressed and the inhibition of food intake diminished. This may be because there are other factors that inhibit food intake besides just the feeling of fullness, such as gastrointestinal discomfort. The most common adverse reaction of GLP-1 RA is gastrointestinal reactions, which gradually decrease with a longer dosing time and are significantly dose-dependent(22). GLP-1 also has a profound inhibitory effect on gastric emptying. The delayed gastric emptying induced by GLP-1 is influenced by a rapid response at the level of vagal activation, and the delay in gastric emptying by GLP-1 is significantly attenuated after long-term administration of GLP-1 analogues(23), which was also consistent with the changes in intake of the intervention groups in this experiment. In addition, PEX-168 is a long-acting preparation with a more sustained hypoglycaemic effect and less effect on gastric emptying, leading to a gradual weakening of the inhibitory effect on food intake.
Insulin resistance
In this study, the hypoglycaemic effect of PEX-168 on simple obese mice manifested at low doses, and all three doses of PEX-168 inhibited the development of prediabetes and improved insulin resistance in nondiabetic simple obese mice. In Khound's animal study(24), it was shown that elevated GLP-1 prevented the overproduction of VLDL and improved insulin resistance induced by a high-fat diet in mice, which is consistent with the results of the present study.
However, clinical trials have confirmed the safety of PEX-168 in regulating blood glucose in T2DM patients, and the risk of hypoglycaemia is very low with monotherapy. In this study, PEX-168 was used in nondiabetic simple obese mice, and hypoglycaemic events occurred in the middle- and high-dose groups, indicating that there is a certain risk of hypoglycaemia when PEX-168 intervenes in simple obese mice with normal blood glucose, and the low dose should be considered the starting dose.
Inflammatory reaction
C-reactive protein is a sensitive marker of systemic inflammation synthesized by the liver. It is a nonspecific acute phase reactant that has traditionally been used to detect acute injury, infection and inflammation(25). Recent studies have shown that diabetes, obesity and elevated levels of CRP, TNF-alpha and leptin are closely associated(26).
In the present study, the level of CRP was significantly elevated in obese mice compared to ND mice, which is consistent with previous reports. The association between obesity and elevated serum CRP levels has been well explained by pathophysiological mechanisms. In this experiment, only the MD and HD groups showed significant improvement in inflammation, and both body weight and the level of CRP in the LD group were not significantly different from those in the HF group, indicating that PEX-168 at medium doses and above significantly reduces body weight in simple obese mice, thereby improving the inflammatory reaction and reducing cardiovascular risk.
Adipose factor
In this study, the level of serum chemerin was significantly higher and the level of serum omentin was significantly lower in obese mice than in the ND group. The concentration of chemerin was associated with BMI, adipocyte volume and number, and in adult obese patients, body weight was significantly and positively correlated with circulating chemerin levels(27). Batista assessed the concentration of omentin in obese patients(28), and normal weight subjects showed higher levels of omentin than overweight and obese patients, which is also consistent with the findings of the study.
Interestingly, although the LD group did not lose weight at the end of the intervention, the levels of FBG, INS, Homa-IR, chemerin and omentin were improved, and the improvements were equal across doses. In Yang's study(29), it was suggested that the GLP-1 analogue liraglutide could improve insulin resistance in high-fat diet-induced obese mice by improving endoplasmic reticulum stress, thereby reducing chemerin levels. K. Tan and Yan pointed out that(21, 30)insulin and glucose could significantly and dose-dependently reduce omentin-1 mRNA and protein levels, and the plasma level of omentin-1 was independently and negatively correlated with fasting insulin and HOMA-IR. K. Tan also pointed out that BMI or WHR is unlikely to be responsible for the decrease in omentin-1 mRNA expression and protein levels in female PCOS patients. In this study, IR was highly and significantly correlated with both chemerin and omentin, so it can be inferred that the regulation of chemerin and omentin expression by PEX-168 may be mainly related to the hypoglycaemic effect of PEX-168, and the weight-reducing effect of PEX-168 is unlikely to be the reason for the changes in both. This conclusion needs to be demonstrated by further experimental studies.
Study strengths and limitations
In this study, the weight reduction effect of PEX-168 was first studied and the effects of it on adipokines chemerin and omentin were further explored. PEX-168 has good potential in treating obesity and preventing the development of diabetes. PEX-168 significantly improves the adipokines mainly through its hypoglycaemic effects. These results provide further mechanistic insight into the action of PEX-168 in the treatment of obesity and diabetes.
However, it has been suggested that(11)non-type 2 diabetic patients lose more weight than type 2 diabetic patients when treated with GLP-1 agonists for weight loss, and this could not be confirmed in this experimental design without the inclusion of a diabetic obesity model group; the intervention period was not long enough. In clinical trials, it was noted that PEX-168 blood levels reached stability after four weeks of intervention, but in this study the measurements of the mice only started to stabilize at a later stage, so the intervention period should be extended.