Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance and glucose intolerance and increases fibroblast growth factor-21 in diet induced obese mice

Chowdhury, S.; Song, S.; Zhang, H. E.; Wang, X. M.; Gall, M. G.; Yu, D. M.-T.; Lay, A. J.; Xiang, M. S.-W.; Evans, K. A.; Wetzel, S.; Liu, Y.; Yau, B.; Coppage, A. L.; Lo, L.; Stokes, R. A.; Hawthorne, W. J.; Cooney, G. J.; McLennan, S. V.; Gunton, J. E.; Bachovchin, W. W.; Turner, N.; Kebede, M. A.; McCaughan, G. W.; Twigg, S. M.; Gorrell, M. D.

doi:10.1101/460279

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bioRxiv · 10.1101/460279

Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance and glucose intolerance and increases fibroblast growth factor-21 in diet induced obese mice

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Abstract

Background & AimsFibroblast activation protein-a (FAP) is a post-proline peptidase closely related to dipeptidyl peptidase-4. FAP degrades bioactive peptides including fibroblast growth factor-21 (FGF-21) and neuropeptide Y. We examined metabolic outcomes of specific genetic ablation of FAP and its enzyme activity in a mouse model of diet-induced obesity (DIO) causing fatty liver.\n\nMethodsWildtype (WT) and genetically modified FAP deficient mice that specifically lacked either the FAP protein or FAP enzyme activity received chow, or an atherogenic diet for 8 to 20 weeks of DIO.\n\nResultsFAP deficient male and female mice in the DIO model were more metabolically healthy than controls. The FAP deficient mice had less glucose intolerance, liver lipid, adiposity, insulin resistance, pancreatic and plasma insulin, pancreatic {beta}-cell hyperplasia, serum alanine transaminase and circulating cholesterol compared to wild type controls. Furthermore, FAP deficiency lowered respiratory exchange ratio and greatly increased intrahepatic non-esterified free fatty acids, indicative of increased lipolysis and {beta}-oxidation. Concordantly, lipogenic genes (Pparg, Gck, Acc, Fasn) and hepatic triglyceride and fatty acid uptake genes (Cd36, Apoc3, Ldlr) and plasma low-density lipoprotein cholesterol were downregulated. Glucagon like peptide-1 levels were unaltered. FAP was localized to human pancreatic {beta}-cells and pancreas from diabetes mellitus patients contained elevated FAP activity. Comparable data from a FAP gene knockout mouse and a novel mouse lacking FAP enzyme activity indicated that these metabolic changes depended upon the enzymatic activity of FAP. These changes may be driven by FGF-21, which was upregulated in livers of FAP deficient DIO mice.\n\nConclusionThis is the first study to show that specific genetic ablation of FAP activity or protein protects against DIO-driven glucose intolerance, hyperinsulinaemia, insulin resistance, hypercholesterolaemia and liver steatosis in mice and provide mechanistic insights.

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Chowdhury, S., Song, S., Zhang, H. E., Wang, X. M., Gall, M. G., Yu, D. M.-T., Lay, A. J., Xiang, M. S.-W., Evans, K. A., Wetzel, S., Liu, Y., Yau, B., Coppage, A. L., Lo, L., Stokes, R. A., Hawthorne, W. J., Cooney, G. J., McLennan, S. V., Gunton, J. E., Bachovchin, W. W., Turner, N., Kebede, M. A., McCaughan, G. W., Twigg, S. M., Gorrell, M. D.. 2018-11-04. Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance and glucose intolerance and increases fibroblast growth factor-21 in diet induced obese mice. https://doi.org/10.1101/460279

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