PT - JOURNAL ARTICLE AU - Sumaiya Chowdhury AU - Sunmi Song AU - Hui Emma Zhang AU - Xin Maggie Wang AU - Margaret G. Gall AU - Denise Ming Tse Yu AU - Angelina J. Lay AU - Michelle Sui Wen Xiang AU - Kathryn A. Evans AU - Stefanie Wetzel AU - Yolanda Liu AU - Belinda Yau AU - Andrew L. Coppage AU - Lisa Lo AU - Rebecca A. Stokes AU - Wayne J. Hawthorne AU - Gregory J. Cooney AU - Susan V. McLennan AU - Jenny E. Gunton AU - William W. Bachovchin AU - Nigel Turner AU - Melkam A. Kebede AU - Geoffrey W. McCaughan AU - Stephen M. Twigg AU - Mark D. Gorrell TI - Fibroblast activation protein enzyme deficiency prevents liver steatosis, insulin resistance and glucose intolerance and increases fibroblast growth factor-21 in diet induced obese mice AID - 10.1101/460279 DP - 2018 Jan 01 TA - bioRxiv PG - 460279 4099 - http://biorxiv.org/content/early/2018/11/04/460279.short 4100 - http://biorxiv.org/content/early/2018/11/04/460279.full AB - Background & Aims Fibroblast 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.Methods Wildtype (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.Results FAP 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 β-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 β-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 β-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.Conclusion This 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.ACCacetyl Co-A carboxylaseApoc3apolipoprotein C3AUCarea under curveBATbrown adipose tissueCd36cluster of differentiation 36DIOdiet induced obesityDPPdipeptidyl peptidaseFAfatty acidFAPfibroblast activation protein-aFGF-21fibroblast growth factor-21Gckglucokinasegkigene knock ingkogene knock outGLP-1glucagon like peptide-1GTTglucose tolerance testH&EHaematoxylin and EosinHFDhigh fat dietHOMAHomeostasis Model AssessmentITTinsulin tolerance testNAFLDnon-alcoholic fatty liver diseaseNASHnon-alcoholic steatohepatitisNEFAnon-esterified free fatty acidNPYneuropeptide YOROoil red OPpargperoxisome proliferator-activated receptor gammaPYYpeptide YYRERrespiratory exchange ratioWATwhite adipose tissueWTwild type