title: The lysyl oxidase inhibitor β-aminopropionitrile reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats.
abstract: Extracellular matrix (ECM) remodelling of the adipose tissue plays a pivotal role in the pathophysiology of obesity. The lysyl oxidase (LOX) family of amine oxidases, including LOX and LOX-like (LOXL) isoenzymes, controls ECM maturation, and upregulation of LOX activity is essential in fibrosis; however, its involvement in adipose tissue dysfunction in obesity is unclear. In this study, we observed that LOX is the main isoenzyme expressed in human adipose tissue and that its expression is strongly upregulated in samples from obese individuals that had been referred to bariatric surgery. LOX expression was also induced in the adipose tissue from male Wistar rats fed a high-fat diet (HFD). Interestingly, treatment with β-aminopropionitrile (BAPN), a specific and irreversible inhibitor of LOX activity, attenuated the increase in body weight and fat mass that was observed in obese animals and shifted adipocyte size toward smaller adipocytes. BAPN also ameliorated the increase in collagen content that was observed in adipose tissue from obese animals and improved several metabolic parameters - it ameliorated glucose and insulin levels, decreased homeostasis model assessment (HOMA) index and reduced plasma triglyceride levels. Furthermore, in white adipose tissue from obese animals, BAPN prevented the downregulation of adiponectin and glucose transporter 4 (GLUT4), as well as the increase in suppressor of cytokine signaling 3 (SOCS3) and dipeptidyl peptidase 4 (DPP4) levels, triggered by the HFD. Likewise, in the TNFα-induced insulin-resistant 3T3-L1 adipocyte model, BAPN prevented the downregulation of adiponectin and GLUT4 and the increase in SOCS3 levels, and consequently normalised insulin-stimulated glucose uptake. Therefore, our data provide evidence that LOX plays a pathologically relevant role in the metabolic dysfunction induced by obesity and emphasise the interest of novel pharmacological interventions that target adipose tissue fibrosis and LOX activity for the clinical management of this disease.
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid 28007, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Miana
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona 08025, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Galán
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid 28007, Spain Cardiovascular Translational Research, NavarraBiomed (Fundación Miguel Servet), Pamplona 31008, Spain.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Martínez-Martínez
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona 08025, Spain.
authors.forename: Saray
authors.initials: S
authors.lastname: Varona
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid 28007, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Jurado-López
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid 28007, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Bausa-Miranda
authors.affiliation: Upper Gastroenterology & Bariatric Surgery Department, Fuenlabrada University Hospital, Madrid 28942, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Antequera
authors.affiliation: Cardiology Department, Cardiovascular Institute, Hospital Clínico San Carlos, Madrid 28040, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Luaces
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona 08025, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Martínez-González
authors.affiliation: Centro de Investigación Cardiovascular (CSIC-ICCC), IIB-Sant Pau, Barcelona 08025, Spain crodriguezs@csic-iccc.org vcara@ucm.es.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid 28007, Spain crodriguezs@csic-iccc.org vcara@ucm.es.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cachofeiro
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000629:Aminopropionitrile / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D048429:Cell Size / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D059305:Diet, High-Fat; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005355:Fibrosis; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D051379:Mice; D008954:Models, Biological; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism*; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D052242:Adiponectin; D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; D007328:Insulin; C495694:Slc2a4 protein, rat; D000629:Aminopropionitrile; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D005947:Glucose
keywords: Adipose tissue; Extracellular matrix; Fibrosis; Insulin resistance; Lysyl oxidase; Obesity