Moncada, R. (Rafael)
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- Uroguanylin prevents hepatic steatosis, mitochondrial dysfunction and fibrosis in obesity-associated NAFLD(Elsevier, 2023) Valenti, V. (Víctor); Colina, I. (Inmaculada); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Fernández-Sáez, E.M. (Eva M.); Losarcos, M. (Maite); Burrell, M.A. (María Ángela); Martín, M. (Mariana); Moncada, R. (Rafael); Mugueta, C. (Carmen); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Escalada, J. (Javier)Background: The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguanylin and guanylin, two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of obesity-associated NAFLD after bariatric surgery. Methods: Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 214 participants undergoing bariatric surgery with biopsy-proven NAFLD diagnosis. Pathways involved in lipid metabolism, mitochondrial network and fibrogenesis were evaluated in liver biopsies (n = 137). The effect of guanylin and uroguanylin on these metabolic functions was assessed in HepG2 hepatocytes and LX-2 hepatic stellate cells (HSC) under lipotoxic and profibrogenic conditions. Results: Plasma and hepatic expression of GUCA2B were decreased in obesity-associated NAFLD. Both GUCA2A and GUCA2B levels were increased after sleeve gastrectomy and Roux-en-Y gastric bypass in parallel to the improved liver function. The liver of patients with type 2 diabetes showed impaired mitochondrial β-oxidation, biogenesis, dynamics as well as increased fibrosis. Uroguanylin diminished the lipotoxicity in palmitate-treated HepG2 hepatocytes, evidenced by decresased steatosis and lipogenic factors, as well as increased mitochondrial network expression, AMPK-induced β-oxidation and oxygen consumption rate. Additionally, uroguanylin, but not guanylin, reversed HSC myofibroblast transdifferentiation as well as fibrogenesis after TGF-β1 stimulation. Conclusions: Uroguanylin constitutes a protective factor against lipotoxicity, mitochondrial dysfunction and fibrosis. Increased GUCA2B levels might contribute to improve liver injury in patients with obesity-associated NAFLD after bariatric surgery.
- Increased expression levels of netrin-1 in visceral adipose tissue during obesity favour colon cancer cell migration(2023) Neira, G. (Gabriela); Valenti, V. (Víctor); Ferro, A. (Alberto); Baixauli-Fons, J. (Jorge); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Mentxaka, A. (Amaia); Becerril, S. (Sara); Frühbeck, G. (Gema); Burrell, M.A. (María Ángela); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Claro, V. (Vasco)Simple Summary Netrin-1 (NTN-1) regulates obesity-associated low-grade inflammation, being also involved in the control of cell migration and proliferation. We aim to study whether excess visceral adipose tissue in patients with obesity and colon cancer is associated with increased NTN1 and the expression levels of its main receptors, promoting an inflammatory microenvironment that favours colon cancer development. Increased expression levels of NTN1 and its receptor NEO1 in the visceral adipose tissue from patients with obesity and colon cancer together with elevated DCC and UNC5B mRNA levels in patients with colon cancer were found. Moreover, the treatment of colorectal cancer cells with NTN-1 and with the adipocyte-derived secretome obtained from patients with obesity increased the migration of colorectal cancer cells. These results suggest that NTN-1 plays an important role in obesity-associated colon cancer development. Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells.
- Dermatopontin, a novel adipokine promoting adipose tissue extracellular matrix remodelling and inflammation in obesity(MDPI AG, 2020) 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)Compelling evidence suggests that dermatopontin (DPT) regulates collagen and fibronectin fibril formation, the induction of cell adhesion and the prompting of wound healing. We aimed to evaluate the role of DPT on obesity and its associated metabolic alterations as well as its impact in visceral adipose tissue (VAT) inflammation and extracellular matrix (ECM) remodelling. Samples obtained from 54 subjects were used in a case-control study. Circulating and VAT expression levels of DPT as well as key ECM remodelling- and inflammation-related genes were analysed. The effect of pro- and anti-inflammatory mediators on the transcript levels of DPT in visceral adipocytes was explored. The impact of DPT on ECM remodelling and inflammation pathways was also evaluated in cultured adipocytes. We show that obesity and obesity-associated type 2 diabetes (T2D) increased (p < 0.05) circulating levels of DPT. In this line, DPT mRNA in VAT was increased (p < 0.05) in obese patients with and without T2D. Gene expression levels of DPT were enhanced (p < 0.05) in human visceral adipocytes after the treatment with lipopolysaccharide, tumour growth factor (TGF)-β and palmitic acid, whereas a downregulation (p < 0.05) was detected after the stimulation with interleukin (IL)-4 and IL-13, critical cytokines mediating anti-inflammatory pathways. Additionally, we revealed that DPT increased (p < 0.05) the expression of ECM- (COL6A3, ELN, MMP9, TNMD) and inflammation-related factors (IL6, IL8, TNF) in human visceral adipocytes. These findings provide, for the first time, evidence of a novel role of DPT in obesity and its associated comorbidities by influencing AT remodelling and inflammation.
- 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.
- 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.
- Decreased Levels of Microfibril-Associated Glycoprotein (MAGP)-1 in Patients with Colon Cancer and Obesity Are Associated with Changes in Extracellular Matrix Remodelling(2021) Unamuno, X. (Xabier); Valenti, V. (Víctor); Baixauli-Fons, J. (Jorge); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Ahechu-Garayoa, P. (Patricia); Mentxaka, A. (Amaia); Gómez-de-Segura, I. (Iranzu); Becerril, S. (Sara); Frühbeck, G. (Gema); Moncada, R. (Rafael); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia)Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 alpha 3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.
- 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.
- Adenoma velloso hipersecretor de recto. Diagnóstico y tratamiento(Arán Ediciones, 2005) Valenti, V. (Víctor); Pastor, C. (Carlos); Poveda, I. (Ignacio); Álvarez-Cienfuegos, J. (Javier); Hernandez-Lizoain, J.L. (Jose Luis); Moncada, R. (Rafael); Gil, A. (Aurora); Cervera, M. (María)
- 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.
- Single anastomosis duodeno-ileal bypass with sleeve gastrectomy generates sustained improvement of glycemic control compared with sleeve gastrectomy in the diet-induced obese rat model(Springer, 2024) Unamuno, X. (Xabier); Valenti, V. (Víctor); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Álvarez-Cienfuegos, J. (Javier); Becerril, S. (Sara); Frühbeck, G. (Gema); Moncada, R. (Rafael); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia)Bariatric surgery has become a recognized and effective procedure for treating obesity and type 2 diabetes (T2D). Our objective was to directly compare the caloric intake-independent effects of sleeve gastrectomy (SG) and single anastomosis duodenoileal bypass with SG (SADI-S) on glucose tolerance in rats with diet-induced obesity (DIO) and to elucidate the differences between bariatric surgery and caloric restriction.A total of 120 adult male Wistar rats with DIO and insulin resistance were randomly assigned to surgical (sham operation, SG, and SADI-S) and dietary (pair-feeding the amount of food eaten by animals undergoing the SG or SADI-S surgeries) interventions. Body weight and food intake were weekly monitored, and 6 weeks after interventions, fasting plasma glucose, oral glucose and insulin tolerance tests, plasma insulin, adiponectin, GIP, GLP-1, and ghrelin levels were determined.The body weight of SADI-S rats was significantly (p < 0.001) lower as compared to the sham-operated, SG, and pair-fed groups. Furthermore, SADI-S rats exhibited decreased whole body fat mass (p < 0.001), lower food efficiency rates (p < 0.001), and increased insulin sensitivity, as well as improved glucose and lipid metabolism compared to that of the SG and pair-fed rats.SADI-S was more effective than SG, or caloric restriction, in improving glycemic control and metabolic profile, with a higher remission of insulin resistance as well as long-term weight loss.