PMID- 29154902 OWN - NLM STAT- MEDLINE DCOM- 20180522 LR - 20181202 IS - 0304-4165 (Print) IS - 0304-4165 (Linking) VI - 1862 IP - 3 DP - 2018 Mar TI - Dipeptidyl peptidase IV (DPP-IV) inhibition prevents fibrosis in adipose tissue of obese mice. PG - 403-413 LID - S0304-4165(17)30377-X [pii] LID - 10.1016/j.bbagen.2017.11.012 [doi] AB - BACKGROUND: During the development of obesity the expansion of white adipose tissue (WAT) leads to a dysregulation and an excessive remodeling of extracellular matrix (ECM), leading to fibrosis formation. These ECM changes have high impact on WAT physiology and may change obesity progression. Blocking WAT fibrosis may have beneficial effects on the efficacy of diet regimen or therapeutical approaches in obesity. Since dipeptidyl peptidase IV (DPP-IV) inhibitors prevent fibrosis in tissues, such as heart, liver and kidney, the objective of this study was to assess whether vildagliptin, a DPP-IV inhibitor, prevents fibrosis in WAT in a mouse model of obesity, and to investigate the mechanisms underlying this effect. METHODS: We evaluated the inhibitory effect of vildagliptin on fibrosis markers on WAT of high-fat diet (HFD)-induced obese mice and on 3T3-L1 cell line of mouse adipocytes treated with a fibrosis inducer, transforming growth factor beta 1 (TGFbeta1). RESULTS: Vildagliptin prevents the increase of fibrosis markers in WAT of HFD-fed mice and reduces blood glucose, serum triglycerides, total cholesterol and leptin levels. In the in vitro study, the inhibition of DPP-IV with vildagliptin, neuropeptide Y (NPY) treatment and NPY Y(1) receptor activation prevents ECM deposition and fibrosis markers increase induced by TGFbeta1 treatment. CONCLUSIONS: Vildagliptin prevents fibrosis formation in adipose tissue in obese mice, at least partially through NPY and NPY Y(1) receptor activation. GENERAL SIGNIFICANCE: This study highlights the importance of vildagliptin in the treatment of fibrosis that occur in obesity. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Marques, Ana Patricia AU - Marques AP AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; PDBEB - Doctoral Program in Experimental Biology and Biomedicine, Institute of Interdisciplinary Research (IIIUC), University of Coimbra, 3004-504 Coimbra, Portugal. FAU - Cunha-Santos, Janete AU - Cunha-Santos J AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. FAU - Leal, Helena AU - Leal H AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal. FAU - Sousa-Ferreira, Ligia AU - Sousa-Ferreira L AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal. FAU - Pereira de Almeida, Luis AU - Pereira de Almeida L AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. FAU - Cavadas, Claudia AU - Cavadas C AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. FAU - Rosmaninho-Salgado, Joana AU - Rosmaninho-Salgado J AD - CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Department of Medical Genetics, Pediatric Unit, Coimbra, Hospital and University Center (CHUC), 3000-602 Coimbra, Portugal. Electronic address: jrosmaninho.salgado@chuc.min-saude.pt. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20171222 PL - Netherlands TA - Biochim Biophys Acta Gen Subj JT - Biochimica et biophysica acta. General subjects JID - 101731726 RN - 0 (Blood Glucose) RN - 0 (Dipeptidyl-Peptidase IV Inhibitors) RN - 0 (Hypolipidemic Agents) RN - 0 (Leptin) RN - 0 (Lipids) RN - 0 (Neuropeptide Y) RN - 0 (Nitriles) RN - 0 (Pyrrolidines) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, Neuropeptide Y) RN - 0 (Transforming Growth Factor beta1) RN - 0 (neuropeptide Y-Y1 receptor) RN - 9007-34-5 (Collagen) RN - EC 3.4.14.5 (Dipeptidyl Peptidase 4) RN - EC 3.4.14.5 (Dpp4 protein, mouse) RN - I6B4B2U96P (Vildagliptin) RN - PJY633525U (Adamantane) SB - IM MH - 3T3-L1 Cells MH - Adamantane/*analogs & derivatives/pharmacology/therapeutic use MH - Adipocytes/drug effects/metabolism MH - Adipose Tissue, White/*drug effects/pathology MH - Animals MH - Blood Glucose/analysis MH - Collagen/metabolism MH - Diet, High-Fat MH - Dipeptidyl Peptidase 4/*drug effects MH - Dipeptidyl-Peptidase IV Inhibitors/pharmacology/*therapeutic use MH - Extracellular Matrix/drug effects/metabolism MH - Fibrosis MH - Hypolipidemic Agents/pharmacology/*therapeutic use MH - Leptin/blood/physiology MH - Lipids/blood MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Obese MH - Neuropeptide Y/agonists/pharmacology/physiology MH - Nitriles/pharmacology/*therapeutic use MH - Obesity/*drug therapy/pathology MH - Pyrrolidines/pharmacology/*therapeutic use MH - RNA Interference MH - RNA, Small Interfering/genetics MH - Receptors, Neuropeptide Y/agonists/physiology MH - Transforming Growth Factor beta1/pharmacology MH - Vildagliptin OTO - NOTNLM OT - Dipeptidyl peptidase IV inhibitor OT - Extracellular matrix OT - Fibrosis OT - Neuropeptide Y OT - Obesity OT - Vildagliptin EDAT- 2017/11/21 06:00 MHDA- 2018/05/23 06:00 CRDT- 2017/11/21 06:00 PHST- 2017/05/04 00:00 [received] PHST- 2017/11/10 00:00 [revised] PHST- 2017/11/13 00:00 [accepted] PHST- 2017/11/21 06:00 [pubmed] PHST- 2018/05/23 06:00 [medline] PHST- 2017/11/21 06:00 [entrez] AID - S0304-4165(17)30377-X [pii] AID - 10.1016/j.bbagen.2017.11.012 [doi] PST - ppublish SO - Biochim Biophys Acta Gen Subj. 2018 Mar;1862(3):403-413. doi: 10.1016/j.bbagen.2017.11.012. Epub 2017 Dec 22.