Artículos de revista (CUN)
Permanent URI for this collectionhttps://hdl.handle.net/10171/70263
See
14 results
Results
- FNDC4 reduces hepatocyte inflammatory cell death via AMPKa in metabolic dysfunction-associated steatotic liver disease(Elsevier Ltd., 2024) Neira, G. (Gabriela); Valenti, V. (Víctor); Colina, I. (Inmaculada); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Escalada, J. (Javier)Background: The molecular mediators responsible for the progression of metabolic dysfunction- associated steatotic liver disease (MASLD) to steatohepatitis (MASH) have not yet been completely disentangled. We sought to analyze whether FNDC4, an hepatokine and adipokine with anti-inflammatory properties, is involved in TNF-a-induced inflammatory cell death in patients with MASLD. Methods: Plasma FNDC4 (n 1⁄4 168) and hepatic FNDC4 and inflammatory cell death (n 1⁄4 65) were measured in samples from patients with severe obesity with available liver biopsy-proven MASLD diagnosis. The effect of FNDC4 on TNF-a-induced pyroptosis, apoptosis and necroptosis (PANoptosis) and mitochondrial dysfunction was studied in vitro using human HepG2 hepatocytes. Results: Compared with individuals with normal liver, patients with type 2 diabetes and MASLD exhibited decreased hepatic FNDC4 mRNA and protein levels, which were related to liver inflammation. An overexpression of TNF-a, its receptor TNF-R1 and factors involved in inflammatory cell death was also found in the liver of these patients. FNDC4-knockdown in HepG2 hepatocytes increased apoptotic cell death, while FNDC4 treatment blunted NLRP3 inflammasome-induced pyroptosis, apoptosis and necroptosis in TNF-a-stimulated hepatocytes. Moreover, FNDC4 improved TNF-a-induced hepatocyte mitochondrial dysfunction by enhancing mitochondrial DNA (mtDNA) copy number and OXPHOS complex subunits I, II, III and V protein expression. Mechanistically, AMP-activated protein kinase a (AMPKa) was required for the FNDC4-mediated inhibition of cell death and increase in mtDNA content. Conclusions: FNDC4 acts as a hepatocyte survival factor favouring mitochondrial homeostasis and decreasing inflammatory cell death via AMPKa. Collectively, our study identifies FNDC4 as an attractive target to prevent hepatocellular damage in patients with MASLD.
- Decreased expression of the NLRP6 inflammasome is associated with increased intestinal permeability and inflammation in obesity with type 2 diabetes(Springer, 2024) Valenti, V. (Víctor); Baixauli-Fons, J. (Jorge); Ramirez, B. (Beatriz); Casado, M. (Marcos); Mentxaka, A. (Amaia); Becerril, S. (Sara); Frühbeck, G. (Gema); Catalán, V. (Víctor); Moncada, R. (Rafael); Reina, G. (Gabriel); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Escalada, J. (Javier)Background Obesity-associated dysfunctional intestinal permeability contributes to systemic chronic infammation leading to the development of metabolic diseases. The infammasomes constitute essential components in the regulation of intestinal homeostasis. We aimed to determine the impact of the infammasomes in the regulation of gut barrier dysfunction and metabolic infammation in the context of obesity and type 2 diabetes (T2D). Methods Blood samples obtained from 80 volunteers (n=20 normal weight, n=21 OB without T2D, n=39 OB with T2D) and a subgroup of jejunum samples were used in a case–control study. Circulating levels of intestinal damage markers and expression levels of infammasomes as well as their main efectors (IL-1β and IL-18) and key infammation-related genes were analyzed. The impact of infammation-related factors, diferent metabolites and Akkermansia muciniphila in the regulation of infammasomes and intestinal integrity genes was evaluated. The efect of blocking NLRP6 by using siRNA in infammation was also studied. Results Increased circulating levels (P<0.01) of the intestinal damage markers endotoxin, LBP, and zonulin in patients with obesity decreased (P<0.05) after weight loss. Patients with obesity and T2D exhibited decreased (P<0.05) jejunum gene expression levels of NLRP6 and its main efector IL18 together with increased (P<0.05) mRNA levels of infammatory markers. We further showed that while NLRP6 was primarily localized in goblet cells, NLRP3 was localized in the intestinal epithelial cells. Additionally, decreased (P<0.05) mRNA levels of Nlrp1, Nlrp3 and Nlrp6 in the small intestinal tract obtained from rats with diet-induced obesity were found. NLRP6 expression was regulated by taurine, parthenolide and A. muciniphila in the human enterocyte cell line CCL-241. Finally, a signifcant decrease (P<0.01) in the expression and release of MUC2 after the knockdown of NLRP6 was observed. Conclusions The increased levels of intestinal damage markers together with the downregulation of NLRP6 and IL18 in the jejunum in obesity-associated T2D suggest a defective infammasome sensing, driving to an impaired epithelial intestinal barrier that may regulate the progression of multiple obesity-associated comorbidities.
- Clinical usefulness of abdominal bioimpedance (ViScan) in the determination of visceral fat and its application in the diagnosis and management of obesity and its comorbidities(Elsevier, 2018) Valenti, V. (Víctor); Colina, I. (Inmaculada); Ramirez, B. (Beatriz); Benito-Boíllos, A. (Alberto); Catalan, V. (Victoria); Frühbeck, G. (Gema); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia); Gil, M.J. (María José); Romero, S. (Sonia); González-Crespo. I. (Ignacio)Background & aims: Visceral adipose tissue (VAT) has been shown to be profoundly responsible of most of the obesity-associated metabolic derangements. The measurement of VAT usually implies the use of imaging techniques such as magnetic resonance imaging or computed tomography (CT). Our aim was to evaluate the accuracy of the determination of VAT by means of abdominal bioimpedance (BIA) with the ViScan device in comparison with CT and its clinical usefulness in the management of obesity. Methods: We studied a sample of 140 subjects (73 males/67 females) with BMI ranging from 17.7 to 50.4 kg/m2 to evaluate the accuracy of the ViScan in comparison to CT to determine VAT. To further analyze ViScan's clinical usefulness we studied a separate cohort (n = 2849) analyzing cardiometabolic risk factors. Furthermore, we studied the ability of the ViScan to detect changes in VAT after weight gain (n = 107) or weight loss (n = 335). The study was performed from October 2009 through June 2015. Results: ViScan determines VAT with a good accuracy in individuals with a CT-VAT up to 200 cm2, and then with lower precision with increasing body mass, exhibiting a moderate-high correlation with CT-VAT (r = 0.75, P < 0.001). Importantly, VAT determination with the ViScan exhibits better correlations with several cardiometabolic risk factors such as glucose, triglycerides, HDL-cholesterol and markers of fatty liver than anthropometric measurements such as BMI or waist circumference. ViScan is able to detect VAT variations after body weight changes. Conclusions: Since the possibility of measuring VAT by imaging techniques is not always available, abdominal BIA represents a good alternative to estimate VAT, allowing the identification of patients with increased VAT-related cardiometabolic risk and a better management of obese patients.
- NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling(Nature Publishing Group, 2021) Unamuno, X. (Xabier); Valenti, V. (Víctor); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia)The NLRP3-IL-1β pathway plays an important role in adipose tissue (AT)-induced inflammation and the development of obesity-associated comorbidities. We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix (ECM) remodeling. Samples obtained from 98 subjects were used in a case-control study. The expression of different components of the inflammasome as well as their main effectors and inflammation- and ECM remodeling-related genes were analyzed. The impact of blocking NLRP3 using siRNA in lipopolysaccharide (LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated. We demonstrated that obesity (P < 0.01), obesity-associated T2D (P < 0.01) and NAFLD (P < 0.05) increased the expression of different components of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT. We also found that obese patients with T2D exhibited increased (P < 0.05) hepatic gene expression levels of NLRP3, IL1B and IL18. We showed that NLRP3, but not NLRP1, is regulated by inflammation and hypoxia in visceral adipocytes. We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked (P < 0.01) LPS-induced inflammation by downregulating the mRNA levels of CCL2, IL1B, IL6, IL8, S100A8, S100A9, TLR4 and TNF as well as inhibiting (P < 0.01) the secretion of IL1-β into the culture medium. Furthermore, blocking NLRP3 attenuated (P < 0.01) the LPS-induced expression of important molecules involved in AT fibrosis (COL1A1, COL4A3, COL6A3 and MMP2). These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.
- Ghrelin Reduces TNF-α-Induced Human Hepatocyte Apoptosis, Autophagy, and Pyroptosis: Role in Obesity-Associated NAFLD(Oxford University Press, 2019) Valenti, V. (Víctor); Ezquerro-Ezquerro, S. (Silvia); Colina, I. (Inmaculada); Catalan, V. (Victoria); Guzmán-Ruiz, R. (Rocío); Becerril, S. (Sara); Frühbeck, G. (Gema); Malagon, M.M. (María M.); Mugueta, C. (Carmen); Mocha, F. (Fátima); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia)Context: Human obesity is associated with increased circulating TNF-α, a proinflammatory cytokine that induces hepatocyte cell death. Objective: The potential beneficial effects of acylated and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-α-induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated. Design, settings, and participants: Plasma ghrelin isoforms and TNF-α were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-α-induced cell death was determined in vitro in human HepG2 hepatocytes. Results: Circulating TNF-α and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and improved hepatic function were found. Patients with obesity and type 2 diabetes showed increased hepatic ghrelin O-acyltransferase transcripts as well as an increased hepatic apoptosis, pyroptosis, and compromised autophagy. In HepG2 hepatocytes, acylated and desacyl ghrelin treatment reduced TNF-α-induced apoptosis, evidenced by lower caspase-8 and caspase-3 cleavage, as well as TUNEL-positive cells and pyroptosis, revealed by decreased caspase-1 activation and lower high-mobility group box 1 expression. Moreover, acylated ghrelin suppressed TNF-α-activated hepatocyte autophagy, as evidenced by a decreased LC3B-II/I ratio and increased p62 accumulation via AMPK/mTOR. Conclusions: Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-α-induced hepatocyte apoptosis, autophagy, and pyroptosis.
- Increased levels of interleukin-36 in obesity and type 2 diabetes fuel adipose tissue inflammation by inducing its own expression and release by adipocytes and macrophages(Frontiers, 2022) Valenti, V. (Víctor); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Mentxaka, A. (Amaia); Becerril, S. (Sara); Frühbeck, G. (Gema); Moncada, R. (Rafael); Reina, G. (Gabriel); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia)Interleukin (IL)-36 is a recently described cytokine with well-known functions in the regulation of multiple inflammatory diseases. Since no data exists on how this cytokine regulates adipose tissue (AT) homeostasis, we aimed to explore the function of a specific isoform, IL-36 gamma, an agonist, in human obesity and obesity-associated type 2 diabetes as well as in AT inflammation and fibrosis.
- Corrigendum: Increased levels of interleukin-36 in obesity and type 2 diabetes fuels adipose tissue inflammation by inducing its own expression and release by adipocytes and macrophages(2023) Valenti, V. (Víctor); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Mentxaka, A. (Amaia); Becerril, S. (Sara); Frühbeck, G. (Gema); Reina, G. (Gabriel); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Moncada-Durruti, R. (Rafael)
- NLRP3 inflammasome: a possible link between obesity-associated low-grade chronic inflammation and colorectal cancer development(NCBI, 2018) Unamuno, X. (Xabier); Marti, P. (Pablo); Baixauli-Fons, J. (Jorge); Catalan, V. (Victoria); Ahechu-Garayoa, P. (Patricia); Zozaya-Larequi, G. (Gabriel); Frühbeck, G. (Gema); Hernandez-Lizoain, J.L. (Jose Luis)Emerging evidence reveals that adipose tissue-associated inflammation is a main mechanism whereby obesity promotes colorectal cancer risk and progression. Increased inflammasome activity in adipose tissue has been proposed as an important mediator of obesity-induced inflammation and insulin resistance development. Chronic inflammation in tumor microenvironments has a great impact on tumor development and immunity, representing a key factor in the response to therapy. In this context, the inflammasomes, main components of the innate immune system, play an important role in cancer development showing tumor promoting or tumor suppressive actions depending on the type of tumor, the specific inflammasome involved, and the downstream effector molecules. The inflammasomes are large multiprotein complexes with the capacity to regulate the activation of caspase-1. In turn, caspase-1 enhances the proteolytic cleavage and the secretion of the inflammatory cytokines interleukin (IL)-1 beta and IL-18, leading to infiltration of more immune cells and resulting in the generation and maintenance of an inflammatory microenvironment surrounding cancer cells. The inflammasomes also regulate pyroptosis, a rapid and inflammation-associated form of cell death. Recent studies indicate that the inflammasomes can be activated by fatty acids and high glucose levels linking metabolic danger signals to the activation of inflammation and cancer development. These data suggest that activation of the inflammasomes may represent a crucial step in the obesity-associated cancer development. This review will also focus on the potential of inflammasome-activated pathways to develop new therapeutic strategies for the prevention and treatment of obesity-associated colorectal cancer development.
- GLP-1 limits adipocyte inflammation and its low circulating pre-operative concentrations predict worse type 2 diabetes remission after bariatric surgery in obese patients(MDPI AG, 2019) Izaguirre, M. (Maitane); Unamuno, X. (Xabier); Valenti, V. (Víctor); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Higuera, M. (Magdalena) de la; Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia); Monreal, J.I. (José Ignacio)Objective: Glucagon-like peptide (GLP)-1 has been proposed as a key candidate in glucose improvements after bariatric surgery. Our aim was to explore the role of GLP-1 in surgically-induced type 2 diabetes (T2D) improvement and its capacity to regulate human adipocyte inflammation. Methods: Basal circulating concentrations of GLP-1 as well as during an oral glucose tolerance test (OGTT) were measured in lean and obese volunteers with and without T2D (n = 93). In addition, GLP-1 levels were determined before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB) (n = 77). The impact of GLP-1 on inflammation signalling pathways was also evaluated. Results: We show that the reduced (p < 0.05) circulating levels of GLP-1 in obese T2D patients increased (p < 0.05) after RYGB. The area under the curve was significantly lower in obese patients with (p < 0.01) and without (p < 0.05) T2D compared to lean volunteers while obese patients with T2D exhibited decreased GLP-1 levels at baseline (p < 0.05) and 120 min (p < 0.01) after the OGTT. Importantly, higher (p < 0.05) pre-operative GLP-1 concentrations were found in patients with T2D remission after RYGB. We also revealed that exendin-4, a GLP-1 agonist, downregulated the expression of inflammation-related genes (IL1B, IL6, IL8, TNF) and, conversely, upregulated the mRNA levels of ADIPOQ in human visceral adipocytes. Furthermore, exendin-4 blocked (p < 0.05) LPS-induced inflammation in human adipocytes via downregulating the expression and secretion of key inflammatory markers. Conclusions: Our data indicate that GLP-1 may contribute to glycemic control and exert a role in T2D remission after RYGB. GLP-1 is also involved in limiting inflammation in human visceral adipocytes.
- Increase of the Adiponectin/Leptin Ratio in Patients with Obesity and Type 2 Diabetes after Roux-en-Y Gastric Bypass(MDPI AG, 2019) Izaguirre, M. (Maitane); Unamuno, X. (Xabier); Valenti, V. (Víctor); Portincasa, P. (Piero); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Salvador, J. (Javier); Rodriguez, A. (Amaia)Bariatric surgery remains the most effective option for achieving important and sustained weight loss. We explored the effects of Roux-en-Y gastric bypass (RYGB) on the circulating levels of adiponectin, leptin, and the adiponectin/leptin (Adpn/Lep) ratio in patients with obesity and type 2 diabetes (T2D). Twenty-five T2D volunteers undergoing RYGB were included in the study, and further subclassified as patients that responded or not to RYBG, regarding remission of T2D. Anthropometric and biochemical variables were evaluated before and after RYGB. Obese patients with T2D exhibited an increase (p < 0.0001) in the Adpn/Lep ratio after RYGB. Changes in the Adpn/Lep ratio correlated better with changes in anthropometric data (p < 0.001) than with the variations of adiponectin or leptin alone. Multiple regression analysis revealed that the change in the Adpn/Lep ratio in patients with T2D was an independent predictor of the changes in body mass index (p < 0.001) and body fat percentage (p = 0.022). However, the Adpn/Lep ratio did not differ between individuals with or without T2D remission after RYGB. In summary, the current study demonstrated that after weight and body fat loss following RYGB, the Adpn/Lep ratio increased in patients with obesity and T2D.