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

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

doi:10.1242/dmm.020107

Cited by 44 publications

(42 citation statements)

References 50 publications

(68 reference statements)

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“…Such alterations included reduced levels of GLUT 4, adiponectin, and GLP‐1 as well as increased levels of DPP4, SOCS3, and IRS‐1 serine phosphorylation. Similar results have previously been described in both human and animal models (13, 16‐18). The relevance of SOCS3 in insulin resistance is confirmed by the fact that its levels were independently associated with HOMA index.…”

Section: Discussionsupporting

confidence: 90%

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The role of mitochondrial oxidative stress in the metabolic alterations in diet‐induced obesity in rats

et al. 2019

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The impact of the mitochondria‐targeted antioxidant MitoQ was evaluated in the metabolic alterations and the adipose tissue remodeling associated with obesity. Male Wistar rats were fed either a high‐fat diet (HFD; 35% fat) or a standard diet (3.5% fat) for 7 wk and treated with MitoQ (200 μM). A proteomic analysis of visceral adipose tissue from patients with obesity and patients without obesity was performed. MitoQ partially prevented the increase in body weight, adiposity, homeostasis model assessment index, and adipose tissue remodeling in HFD rats. It also ameliorated protein level changes of factors involved in insulin signaling observed in adipose tissue of obese rats: reductions in adiponectin and glucose transporter 4 (GLUT 4) and increases in dipeptidylpeptidase 4, suppressor of cytokine signaling 3 (SOCS3), and insulin receptor substrate 1 phosphorylation. MitoQ prevented down‐regulation of adiponectin and GLUT 4 and increases in SOCS3 levels in a TNF‐α‐induced insulin‐resistant 3T3‐L1 adipocyte model. MitoQ also ameliorated alterations in mitochondrial proteins observed in obese rats: increases in cyclophylin F and carnitine palmitoyl transferase 1A and reductions in mitofusin1, peroxiredoxin 4, and fumarate hydratase. The proteomic analysis of the visceral adipose tissue from patients with obesity show alterations in mitochondrial proteins similar to those observed in obese rats. Therefore, the data show the beneficial effect of MitoQ in the metabolic dysfunction induced by obesity.—Marín‐Royo, G., Rodríguez, C., Le Pape, A., Jurado‐Lopez, R., Luaces, M., Antequera, A., Martinez‐Gonzalez, J., Souza‐Neto, F. V., Nieto, M. L., Martínez‐Martínez, E., Cachofeiro, V. The role of mitochondrial oxidative stress in the metabolic alterations in diet‐induced obesity in rats. FASEB J. 33, 12060‐12072 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 90%

“…For the TNF‐α treatment (72 h), fully differentiated 3T3‐L1 adipocytes were treated every 24 h with the cytokine as previously described by Miana et al. (13), MitoQ (50 nM) was added to TNF‐α‐treated cells during the last 24 h of incubation.…”

Section: Methodsmentioning

confidence: 99%

The role of mitochondrial oxidative stress in the metabolic alterations in diet‐induced obesity in rats

et al. 2019

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“…In fact, changes in Lox activity involved in the dysfunction of adipocyte in obesity. Recent reports showed that Lox is upregulated in adipose tissue from individuals with obesity . The inhibition of Lox activity through β‐aminopropionitrile (BAPN, a specific and irreversible inhibitor of Lox activity) attenuates the increase in body weight and fat mass, reduces adipose tissue fibrosis, and partially corrects the adipocyte‐size distribution pattern.…”

Section: Discussionmentioning

confidence: 99%

miR‐27 impairs the adipogenic lineage commitment via targeting lysyl oxidase

Chen

Ning

et al. 2015

Obesity

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Objective: The recruitment and commitment of mesenchymal stem cells and their terminal differentiation into adipocytes are the main pathways for increasing adipocyte cell numbers during obesity. Our previous studies have shown that lysyl oxidase (Lox) is upregulated and functions as an essential factor during bone morphogenetic protein 4 (BMP4) -induced C3H10T1/2 cell adipocytic lineage commitment. However, the mechanism of Lox regulation during adipogenic lineage commitment has remained largely unestablished. Methods: Samples of adipose tissue from humans with different BMI and C57BL/6 mice with a high-fat diet were used to compare microRNA-27 (miR-27) expression level associated with obesity. Taqman assays were used for miR-27 expression detection and Oil Red O staining for adipogenesis analysis. Results: A negative correlation was identified between Lox expression level and miR-27 expression in both BMP4-treated C3H10T1/2 cells and human subcutaneous adipose tissues. A Lox 3 0 UTR luciferase reporter assay showed that miR-27 directly targeted Lox. Furthermore, overexpression of miR-27 impaired BMP4-induced upregulation of Lox and adipocytic commitment, which could be rescued by overexpression of mature Lox. Conversely, miR-27 inhibition by specific inhibitors increased Lox expression and adipocytic commitment. Conclusions: Taken together, these results suggest a novel role for miR-27 in repressing adipogenic lineage commitment by targeting Lox.

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“…Lysyl oxidase (LOX) and lysyl oxidase-like 1–4 (LOXL1–4) proteins mediate the cross-linking of collagens and/or elastin and are thus relevant in the remodeling of the ECM ( 13 ). Only LOX ( 9 , 14 ) and LOXL1 ( 15 ) have been described to be expressed in AT. LOX is a secreted protein that is down-regulated within the first phase of adipocyte differentiation ( 9 , 16 ).…”

mentioning

confidence: 99%

“…In obese AT, LOX expression is up-regulated in a hypoxia-dependent manner and is implicated in tissue fibrosis ( 9 ). Inhibition of systemic LOX activity with β-aminopropionitrile reduced body weight and improved the metabolic profile in obese rats ( 14 ). However, nothing is known about other lysyl oxidase family members in the context of AT ECM.…”

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confidence: 99%

APMAP interacts with lysyl oxidase–like proteins, and disruption ofApmapleads to beneficial visceral adipose tissue expansion

et al. 2017

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Adipocyte plasma membrane–associated protein (APMAP) has been described as an adipogenic factor in 3T3-L1 cells with unknown biochemical function; we therefore aimed to investigate the physiologic function of APMAP in vivo. We generated Apmap-knockout mice and challenged them with an obesogenic diet to investigate their metabolic phenotype. We identified a novel truncated adipocyte-specific isoform of APMAP in mice that is produced by alternative transcription. Mice lacking the full-length APMAP protein, the only isoform that is expressed in humans, have an improved metabolic phenotype upon diet-induced obesity, indicated by enhanced insulin sensitivity, preserved glucose tolerance, increased respiratory exchange ratio, decreased inflammatory marker gene expression, and reduced adipocyte size. At the molecular level, APMAP interacts with the extracellular collagen cross-linking matrix proteins lysyl oxidase–like 1 and 3. On a high-fat diet, the expression of lysyl oxidase–like 1 and 3 is strongly decreased in Apmap-knockout mice, paralleled by reduced expression of profibrotic collagens and total collagen content in epididymal white adipose tissue, indicating decreased fibrotic potential. Together, our data suggest that APMAP is a novel regulator of extracellular matrix components, and establish that APMAP is a potential target to mitigate obesity-associated insulin resistance.—Pessentheiner, A. R., Huber, K., Pelzmann, H. J., Prokesch, A., Radner, F. P. W., Wolinski, H., Lindroos-Christensen, J., Hoefler, G., Rülicke, T., Birner-Gruenberger, R., Bilban, M., Bogner-Strauss, J. G. APMAP interacts with lysyl oxidase–like proteins, and disruption of Apmap leads to beneficial visceral adipose tissue expansion.

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

Cited by 44 publications

References 50 publications

The role of mitochondrial oxidative stress in the metabolic alterations in diet‐induced obesity in rats

The role of mitochondrial oxidative stress in the metabolic alterations in diet‐induced obesity in rats

miR‐27 impairs the adipogenic lineage commitment via targeting lysyl oxidase

APMAP interacts with lysyl oxidase–like proteins, and disruption ofApmapleads to beneficial visceral adipose tissue expansion

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