Fibroblast activation protein (FAP) as a novel metabolic target.
OBJECTIVE
Fibroblast activation protein (FAP) is a serine protease belonging to a S9B prolyl oligopeptidase subfamily. This enzyme has been implicated in cancer development and recently reported to regulate degradation of FGF21, a potent metabolic hormone. Using a known FAP inhibitor, talabostat (TB), we explored the impact of FAP inhibition on metabolic regulation in mice.


METHODS
To address this question we evaluated the pharmacology of TB in various mouse models including those deficient in FGF21, GLP1 and GIP signaling. We also studied the ability of FAP to process FGF21 in vitro and TB to block FAP enzymatic activity.


RESULTS
TB administration to diet-induced obese (DIO) animals led to profound decreases in body weight, reduced food consumption and adiposity, increased energy expenditure, improved glucose tolerance and insulin sensitivity, and lowered cholesterol levels. Total and intact plasma FGF21 were observed to be elevated in TB-treated DIO mice but not lean animals where the metabolic impact of TB was significantly attenuated. Furthermore, and in stark contrast to naïve DIO mice, the administration of TB to obese FGF21 knockout animals demonstrated no appreciable effect on body weight or any other measures of metabolism. In support of these results we observed no enzymatic degradation of human FGF21 at either end of the protein when FAP was inhibited in vitro by TB.


CONCLUSIONS
We conclude that pharmacological inhibition of FAP enhances levels of FGF21 in obese mice to provide robust metabolic benefits not observed in lean animals, thus validating this enzyme as a novel drug target for the treatment of obesity and diabetes.
Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Munich, 85748, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, 85748, Germany; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany.
Miguel Angel
MA
Sánchez-Garrido
Department of Medicine Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, AL, 35294, United States.
Kirk M
KM
Habegger
Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Munich, 85748, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, 85748, Germany; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany.
Christoffer
C
Clemmensen
Department of Medicine Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, AL, 35294, United States.
Cassie
C
Holleman
Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Munich, 85748, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, 85748, Germany; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany.
Timo D
TD
Müller
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45237, United States.
Diego
D
Perez-Tilve
Department of Chemistry, Indiana University, Bloomington, IN, 46405, United States.
Pengyun
P
Li
Department of Chemistry, Indiana University, Bloomington, IN, 46405, United States.
Archita S
AS
Agrawal
Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Munich, 85748, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, 85748, Germany; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany.
Brian
B
Finan
Lunenfeld Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, 600 University Ave, TCP5-1004 Mailbox 39, Toronto, Ontario, M5G 1X5, Canada.
Daniel J
DJ
Drucker
Institute for Diabetes and Obesity (IDO), Helmholtz Diabetes Center, Munich, 85748, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, 85748, Germany; German Center for Diabetes Research (DZD), Neuherberg, 85764, Germany.
Matthias H
MH
Tschöp
Department of Chemistry, Indiana University, Bloomington, IN, 46405, United States. Electronic address: rdimarch@indiana.edu.
Richard D
RD
DiMarchi
Department of Chemistry, Indiana University, Bloomington, IN, 46405, United States. Electronic address: alexkhar@indiana.edu.
Alexei
A
Kharitonenkov
DPP4; Diabetes; FAP; FGF21; Metabolic regulation; Obesity
Endocrinology. 2015 Jun;156(6):2087-102
25774553
Bioorg Med Chem Lett. 2006 Mar 1;16(5):1346-9
16332437
FEBS Lett. 2009 Jan 5;583(1):19-24
19059246
Nat Methods. 2011 Dec 28;9(1):57-63
22205519
Mol Cancer Ther. 2005 Mar;4(3):351-60
15767544
Biochem Biophys Res Commun. 2007 Aug 24;360(2):437-40
17601491
Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1105-14
19706786
FEBS Open Bio. 2013 Dec 08;4:43-54
24371721
Blood. 2006 Feb 15;107(4):1397-404
16223769
Cell Metab. 2013 Sep 3;18(3):333-40
24011069
Cancer Res. 2004 Aug 1;64(15):5471-80
15289357
Int J Cancer. 1994 Aug 1;58(3):385-92
7519584
Mol Metab. 2013 Dec 27;3(3):221-9
24749049
Expert Opin Investig Drugs. 2007 Sep;16(9):1459-65
17714031
Cell Metab. 2007 Jun;5(6):426-37
17550778
Diabetes. 2010 Nov;59(11):2781-9
20682689
Cancer Res. 1986 Dec;46(12 Pt 1):6406-12
2877731
Endocrinology. 2009 Nov;150(11):4931-40
19819944
Mol Cancer Ther. 2012 Feb;11(2):257-66
22323494
Anal Chem. 2013 Mar 5;85(5):2731-8
23373459
Cancer Biol Ther. 2007 Nov;6(11):1691-9
18032930
PLoS One. 2016 Mar 10;11(3):e0151269
26962859
J Cell Physiol. 2009 May;219(2):227-34
19117008
Cancer Biol Ther. 2012 Feb 1;13(3):123-9
22236832
Diabetes. 2009 Jan;58(1):250-9
18840786
Diabetes. 2013 May;62(5):1453-63
23305646
Endocrinology. 2008 Dec;149(12):6018-27
18687777
Bioorg Med Chem Lett. 2012 May 15;22(10):3412-7
22525314
Proteomics Clin Appl. 2014 Jun;8(5-6):454-63
24470260
Curr Diabetes Rev. 2012 Jul 1;8(4):285-93
22587513
Endocr Rev. 2014 Dec;35(6):992-1019
25216328
Proc Natl Acad Sci U S A. 1990 Sep;87(18):7235-9
2402505
J Biol Chem. 2016 Mar 11;291(11):5986-96
26797127
Br J Clin Pharmacol. 2015 Nov;80(5):1051-63
25940675
Biochem J. 2016 Mar 1;473(5):605-14
26635356
Peptides. 2016 Jan;75:80-95
26621486
Cell Metab. 2016 Mar 8;23 (3):427-40
26959184
Mol Cell Biol. 2000 Feb;20(3):1089-94
10629066
J Clin Invest. 2005 Jun;115(6):1627-35
15902306
Cell Metab. 2007 Jun;5(6):415-25
17550777
Diabetes. 2006 Jun;55(6):1695-704
16731832
PLoS One. 2013;8(3):e58575
23536797
PLoS One. 2015 Mar 19;10(3):e0119104
25790234
PLoS One. 2012;7(11):e49345
23209571
Curr Top Med Chem. 2011;11(12):1447-63
21510839
FEBS J. 2011 Apr;278(8):1316-32
21314817