The lysyl oxidase inhibitor β-aminopropionitrile reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats.

María Miana,Cristina Rodríguez,Saray Varona,Raquel Jurado-López,Ernesto Martínez-Martínez,Belén Bausa-Miranda,María Galán,María Luaces,José Martínez-González,Victoria Cachofeiro,Alfonso Antequera

doi:10.1242/dmm.020107

Abstract

ABSTRACTExtracellular 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.

Highlights

In recent years, there has been increasing evidence that the extracellular matrix (ECM) plays a key role in adipose tissue development and function, and fibrosis is recognised as a crucial player in adipose tissue dysfunction in obesity
Lysyl oxidase (LOX) inhibition improves multiple metabolic parameters: normalizing glucose, insulin and triglyceride levels and reducing the homeostatic model assessment (HOMA) index – a measure of insulin resistance. In these animals, BAPN ameliorates the disturbances in the adipose tissue expression of adiponectin, glucose transporter 4 (GLUT4), suppressor of cytokine signaling 3 (SOCS3) and dipeptidyl peptidase 4, all proteins involved in the control of insulin sensitivity
The mean age of the obese group was BAPN ameliorates the increase in body weight, adiposity and adipose tissue fibrosis in high-fat diet (HFD)-fed rats To investigate whether LOX contributes to the adipose tissue dysfunction associated with obesity, rats subjected to a HFD were treated with BAPN, an irreversible and specific inhibitor of LOX activity

Summary

Introduction

There has been increasing evidence that the extracellular matrix (ECM) plays a key role in adipose tissue development and function, and fibrosis is recognised as a crucial player in adipose tissue dysfunction in obesity. Five isoenzymes belonging to the LOX family have been identified, including LOX, LOX-like (LOXL1), LOXL2, LOXL3 and LOXL4 They are copperdependent amine oxidases that exhibit a high degree of homology in the C-terminal domain, which contains the catalytic site. LOX, the archetypal member of this family and the best characterised, catalyses the covalent cross-linking of collagens and elastin fibres (Rodríguez et al, 2008a,b). This enzyme oxidises lysine and hydroxylysine residues in these substrates, leading to the synthesis of highly reactive peptidylsemialdehydes that can spontaneously condense to form the intra- and intermolecular covalent crosslinkages that are responsible for ECM stability. The disturbance of LOX activity induces connective tissue abnormalities related to pathological processes, including cardiovascular diseases, as we have previously described (Miana et al, 2011; Orriols et al, 2014; Raposo et al, 2004; Rodriguez et al, 2002, 2009; Stefanon et al, 2013)

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