Artículos de revista (CUN)
Permanent URI for this collectionhttps://hdl.handle.net/10171/70263
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- 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.
- Cardiometabolic risk stratification using a novel obesity phenotyping system based on body adiposity and waist circumference(Elsevier B.V., 2024) Marugan-Pinos, R. (Rocío); Perdomo-Zelaya, C.M. (Carolina M.); Ramirez, B. (Beatriz); Catalan, V. (Victoria); Aguas-Ayesa, M. (Maite); Becerril, S. (Sara); Frühbeck, G. (Gema); Olazarán, L. (Laura); Salmón-Gómez, L. (Laura); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Escalada, J. (Javier); Yárnoz-Esquiroz, P. (Patricia)Background: The estimation of obesity-associated cardiometabolic risk does not usually take into account body composition or the distribution of adiposity. The aim of the present study was to assess the clinical usefulness of a novel obesity phenotyping system based on the combination of actual body fat percentage (BF%) and waist circumference (WC) according to the cardiometabolic risk estimation. Methods: A classification matrix combining BF% and WC as measures of both amount and distribution of adiposity establishing nine body phenotypes (3 BF% x 3 WC) was developed. Individuals were grouped in five different cardiometabolic risk phenotypes. We conducted a validation study in a large cohort of White subjects from both genders representing a wide range of ages and adiposity (n = 12,754; 65 % females, aged 18–88 years). Results: The five risk groups using the matrix combination of BF% and WC exhibited a robust linear distribution regarding cardiometabolic risk, estimated by the Metabolic Syndrome Severity Score, showing a continuous increase between groups with significant differences (P < 0.001) among them, as well as in other cardiometabolic risk factors. An additional 24 % of patients at very high risk was detected with the new classification system proposed (P < 0.001) as compared to an equivalent matrix using BMI and WC instead of BF% and WC. Conclusions: A more detailed phenotyping should be a priority in the diagnosis and management of patients with obesity. Our classification system allows to gradually estimate the cardiometabolic risk according to BF% and WC, thus representing a novel and useful tool for both research and clinical practice.
- Antagonic effect of ghrelin and LEAP-2 on hepatic stellate cell activation and liver fibrosis in obesity-associated nonalcoholic fatty liver disease(Oxford University Press, 2023) Landecho, M.F. (Manuel F.); Valenti, V. (Víctor); Ezquerro-Ezquerro, S. (Silvia); Hanley, K.P. (Karen Piper); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Tuero, C. (Carlota); Mocha, F. (Fátima); Silva, C. (Camilo); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Escalada, J. (Javier); Moncada-Durruti, R. (Rafael)Background: Growing evidence suggests the key role of ghrelin in the onset and progression of nonalcoholic fatty liver disease (NAFLD). The potential participation of ghrelin and the ghrelin receptor antagonist, LEAP-2, in the onset of liver fibrosis in patients with severe obesity and NAFLD through the regulation of TGF-β1-induced hepatic stellate cell (HSC) activation was investigated.
- Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD(2020) Sánchez-Infantes, D. (David); Bartrons, R. (Ramon); Valenti, V. (Víctor); Domínguez-Castellano, M. (María); Weber, M. (Minéia); Frühbeck, G. (Gema); Zorzano, A. (Antonio); Fucho, R. (Raquel); Casals, N. (Núria); Llorente-Cortes, V. (Vicenta); Mera, P. (Paula); Soler-Vázquez, M.C. (M. Carmen); Serra, D. (Dolors); Herrero, L. (Laura); Mir, J.F. (Joan Francesc); Rodriguez, A. (Amaia); Sebastián, D. (David); Montironi, C. (Carla); Casas, J. (Josefina); Alonso, S. (Sergio); Recalde, S. (Sandra); Escola-Gil, J.C. (Joan Carles)The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high-fat diet (HFD)-induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno-associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD-induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9-hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD-induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans.
- 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.
- Effect of obesity on clinical characteristics of primary aldosteronism patients at diagnosis and postsurgical responsei(2023) Díaz-Guardiola, P. (Patricia); Morales, M. (Manuel); Perdomo-Zelaya, C.M. (Carolina M.); Ferreira, R. (Rui); Percovich, J.C. (Juan Carlos); Ruiz-Sanchez, J.G. (Jorge Gabriel); Manjón, L. (Laura); Picón-César, M.J. (María José); González-Boillos, M. (Marga); Martín-Rojas-Marcos, P. (Patricia); Hanzu, F. (Felicia); Gracia-Gimeno, P. (Paola); Gómez-Hoyos, E. (Emilia); García-Sanz, I. (Íñigo); Pla-Peris, B. (Begoña); Vicente-Delgado, A. (Almudena); Recasens, M. (Mónica); Araujo-Castro, M. (Marta); Pascual-Corrales, E. (Eider); Parra-Ramírez, P. (Paola); García-Centeno, R. (Rogelio); Rebollo-Román, A. (Angel); García-Cano, A.M. (Ana María); Paja, M. (Miguel); Barahona-San-Millan, R. (Rebeca); García-González, J.J. (Juan Jesús); Robles-Lázaro, C. (Cristina)BACKGROUND: Patients with obesity have an overactivated renin-angiotensin-aldosterone system (RAAS) that is associated with essential hypertension. However, the influence of obesity in primary aldosteronism (PA) is unknown. We analyzed the impact of obesity on the characteristics of PA, and the association between obesity and RAAS components. METHODS: Retrospective study of the Spanish PA Registry (SPAIN-ALDO Registry), which included patients with PA seen at 20 tertiary centers between 2018-2022. Differences between patients with and without obesity were analyzed. RESULTS: 415 patients were included; 189 (45.5%) with obesity. Median age: 55 years [47.3-65.2] and 240 (58.4%) were male. Compared to those without obesity, patients with obesity had higher rates of diabetes mellitus, chronic kidney disease, obstructive apnea syndrome, left ventricular hypertrophy, prior cardiovascular events, higher means of systolic blood pressure (BP) and required more antihypertensive drugs. Patients with PA and obesity also had higher values of serum glucose, HbA1c, creatinine, uric acid, and triglycerides, and lower levels of HDL-cholesterol. Levels of blood aldosterone (PAC) and renin were similar between patients with and without obesity. Body mass index was not correlated with PAC nor renin. The rates of adrenal lesions on imaging studies, as well as the rates of unilateral disease assessed by adrenal vein sampling or I-6beta-iodomethyl-19-norcholesterol scintigraphy were similar between groups. CONCLUSION: Obesity in PA patients involves a worse cardiometabolic profile, and need for more antihypertensive drugs but similar PAC and renin levels, and rates of adrenal lesions and lateral disease than patients without obesity. However, obesity implicates a lower rate of hypertension cure after adrenalectomy.
- Adipokine dysregulation and adipose tissue inflammation in human obesity(Wiley, 2018) Unamuno, X. (Xabier); Catalan, V. (Victoria); Becerril, S. (Sara); Frühbeck, G. (Gema); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia)Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including type 2 diabetes, cardiovascular diseases, nonalcoholic fatty liver disease and cancer. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins and growth and vasoactive factors, collectively termed adipokines that influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodelling and fibrosis together with an altered secretion of adipokines. This review describes how adipose tissue becomes inflamed in obesity and summarizes key players and molecular mechanisms involved in adipose inflammation.
- Contemporary medical, device, and surgical therapies for obesity in adults(Elsevier, 2023) Perdomo-Zelaya, C.M. (Carolina M.); Cohen, R.V. (Ricardo V.); Frühbeck, G. (Gema); Clement, K. (K.); Sumithran, P. (Priya)The goal of obesity management is to improve health. Sustained weight loss of more than 10% overall bodyweight improves many of the complications associated with obesity (eg, prevention and control of type 2 diabetes, hypertension, fatty liver disease, and obstructive sleep apnoea), as well as quality of life. Maintenance of weight loss is the major challenge of obesity management. Like all chronic diseases, managing obesity requires a long-term, multimodal approach, taking into account each individual's treatment goals, and the benefit and risk of different therapies. In conjunction with lifestyle interventions, anti-obesity medications and bariatric surgery improve the maintenance of weight loss and associated health gains. Most available anti-obesity medications act on central appetite pathways to reduce hunger and food reward. In the past 5 years, therapeutic advances have seen the development of targeted treatments for monogenic obesities and a new generation of anti-obesity medications. These highly effective anti-obesity medications are associated with weight losses of more than 10% of overall bodyweight in more than two-thirds of clinical trial participants. Long-term data on safety, efficacy, and cardiovascular outcomes are awaited. Long-term studies have shown that bariatric surgical procedures typically lead to a durable weight loss of 25% and rapid, sustained improvements in complications of obesity, although they have not yet been compared with new-generation highly effective anti-obesity medications. Further work is required to determine optimal patient-specific treatment strategies, including combinations of lifestyle interventions, anti-obesity medications, endoscopic and bariatric surgical procedures, and to ensure equitable access to effective treatments.
- 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.