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[Engadin]

F U L L    T E X T  :   ScienceDirect

 

 

HIGHLIGHTS

 

 

• Acute inhibition of FAP enzyme activity improves glucose tolerance in mice.
• Fap knockout mice exhibit normal glucose and lipid tolerance.
• Fap knockout mice do not resist obesity after high fat feeding.
• Talabostat robustly lowers glucose in a FAP and FGF21-independent manner.
• Talabostat, but not CPD60, requires DPP4 to exert its full metabolic activity.

 

 

Abstract

 

 

Objective

 

Fibroblast Activation Protein (FAP), an enzyme structurally related to dipeptidyl peptidase-4 (DPP-4), has garnered interest as a potential metabolic drug target due to its ability to cleave and inactivate FGF-21 as well as other peptide substrates. Here we investigated the metabolic importance of FAP for control of body weight and glucose homeostasis in regular chow-fed and high fat diet-fed mice.

 

 

Methods

 

FAP enzyme activity was transiently attenuated using a highly-specific inhibitor CPD60 and permanently ablated by genetic inactivation of the mouse Fap gene. We also assessed the FAP-dependence of CPD60 and talabostat (Val-boroPro), a chemical inhibitor reportedly targeting both FAP and dipeptidyl peptidase-4.

 

 

Results

 

CPD60 robustly inhibited plasma FAP activity with no effect on DPP-4 activity. Fapgene disruption was confirmed by assessment of genomic DNA, and loss of FAP enzyme activity in plasma and tissues. CPD60 did not improve lipid tolerance but modestly improved acute oral and intraperitoneal glucose tolerance in a FAP-dependent manner. Genetic inactivation of Fap did not improve glucose or lipid tolerance nor confer resistance to weight gain in male or female Fap−/− mice fed regular chow or high-fat diets. Moreover, talabostat markedly improved glucose homeostasis in a FAP- and FGF-21-independent, DPP-4 dependent manner.

 

 

Conclusion

 

Although pharmacological FAP inhibition improves glucose tolerance, the absence of a metabolic phenotype in Fap−/− mice suggest that endogenous FAP is dispensable for the regulation of murine glucose homeostasis and body weight. These findings highlight the importance of characterizing the specificity and actions of FAP inhibitors in different species and raise important questions about the feasibility of mouse models for targeting FAP as a treatment for diabetes and related metabolic disorders.