Incretin-FGF21 fusion molecule maximizes metabolic effects in mice

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The first dose administration of Trulicity and triple agonist (LG21 and DG21) resulted in significant decreases in blood glucose levels (Figure 1A).Mono (Trulicity, pro21, and euk21) and dual (L21 and D21) agonists significantly reduced fasting blood glucose levels (Figure 1B).Mono (euk21) and dual (L21 and D21) agonist treatment also significantly increased intraperitoneal glucose tolerance (Figure 1C) and insulin sensitivity (Figure 1D).However, the effect of triple agonists (LG21 and DG21) largely disappeared after multiple-dose administration (Figure 1).These data suggested that dulaglutide alone or in combination with FGF21 can effectively improve glucose metabolism.Although D21 seems to be less effective than Trulicity (Table 1; glycemic parameter score), the fact that Trulicity is a drug formulation and D21 is a pure protein may account for the slight difference.
Treatment with mono (Trulicity, pro21, and euk21) and dual (L21 and D21) agonists lowered the levels of triacylglycerol, total cholesterol, and low-density lipoprotein more prominently in the liver than in the blood (Figure 2A).The dulaglutide-FGF21 (D21) fusion protein is the most effective, followed by euk21 and then Trulicity (Table 1); hence, FGF21 appeared to have a greater impact than dulaglutide on lipid metabolism.
Treatment with mono (Trulicity, pro21, and euk21) and dual (L21 and D21) agonists significantly reduced body and liver weights (Figure 2B,C).However, reductions in adipose tissue weight were only significant in the groups with euk21 and D21 (Figure 2C).Greater than 30% reductions in body weight were observed in the euk21-and D21-treated groups (Figure 2B).FGF21 was seen to have a higher impact than dulaglutide on organ weights (Table 1).No significant food intake difference was observed in the treated groups compared to the high-fat diet (HFD) group.However, a difference was noticeable between the Trulicity and G21 groups (Figure 2D).Some studies have reported that GLP-1R [5] or GIPR [6] activation reduces food intake.It is unclear why G21 treatment leads to higher food intake than Trulicity treatment.
Mono (Trulicity and euk21) and dual (L21 and D21) agonist treatment significantly reduced liver levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), as well as blood levels of ALT and ALP (Supplementary Figure S2A) and nonalcoholic fatty liver score (NAS) and fibrosis score (Supplementary Figure S2B).FGF21 again had a more marked effect than dulaglutide on liver function parameters (Table 1).
In summary, we found that dulaglutide (Trulicity) had the most significant effect on reducing glycemic parameters (Table 1).FGF21 alone (euk21) or in combination with dulaglutide (D21) had greater impacts than Trulicity on lipid metabolism, organ weights and liver functions.D21 had the most significant overall impact among the fusion proteins tested in our experiments (Table 1).We noticed that eukaryotically expressed euk21 had a greater impact on metabolism than prokaryotically expressed pro21, possibly due to stabilization of the euk21 protein through Fc dimerization.We observed that the dulaglutide-FGF21 fusion had the highest activity, followed by the liraglutide-FGF21 fusion.Molecules fused with GIP, either the

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Incretin-FGF21 maximizes metabolic effects in mice GIP-FGF21 dual agonist or the GLP-1 (dulaglutide or liraglutide)-GIP-FGF21 triple agonists, were basically ineffective under our experimental conditions.Incretin receptor agonists such as tirzepatide offer effective pharmacological control of obesity but may be less effective for the treatment of NASH [7].FGF21 analogs are effective for the treatment of NASH [4,8].Our study indicated that D21 has a significant impact on glucose and lipid metabolism, body weight and liver function.Incretin-FGF21 combinatory agonists may effectively control common metabolic diseases and thus warrant further investigation.Incretin-FGF21 maximizes metabolic effects in mice 147

Figure 2 .
Figure 2. Effects of fusion proteins on lipid metabolism and organ weight (A) Box and whisker graph of blood and liver levels of triacylglycerols (TG), total cholesterol (TC), and low-density lipoprotein (LDL).(B) Body weight, area under the curve, and percent of body weight change.(C) Box and whisker graph of the liver, inguinal white adipose tissue (WAT) and perigonadal WAT weights.(D) Box and whisker graph of diet intake.Box and whisker graphs show the highest, the lowest, 25% and 75% quartile, and median values.*P<0.05,**P<0.01,***P<0.001,****P<0.0001.