Depósito Académico
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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.
- Comment on: “Pregnancy outcomes after bariatric surgery: importance of maternal ferritin on birth weight”(Springer, 2024) Aguas-Ayesa, M. (Maite); Frühbeck, G. (Gema); Gomez-Ambrosi, J. (Javier)Of all the available therapies, in adequately selected patients, bariatric surgery (BS) is the most efective treatment for severe obesity and its complications. Despite the numerous benefits of BS, even in reproductive performance, women who have undergone BS have higher rates of small-for-gestational age (SGA) fetuses and preterm births than non-intervened women with the same body mass index (BMI). The mechanisms involved are not known, but nutritional defciencies, common after BS, have been identifed as one of the factors that could contribute to these pregnancy complications.
- Revisiting the beyond BMI paradigm in excess weight diagnosis and management: A call to action(John Wiley & Sons, 2024) Aguas-Ayesa, M. (Maite); García-Almeida, J.M. (José Manuel); Frühbeck, G. (Gema); Olazarán, L. (Laura); Perdomo, C. (Carolina); Gomez-Ambrosi, J. (Javier); Vegas-Aguilar, I.M. (Isabel María); Yárnoz-Esquiroz, P. (Patricia)Adolphe Quételet, a 19th-century Belgian sociologist and statistician, pioneered the incorporation of statistics into social sciences. He initiated the development of anthropometry since he was interested in identifying the proportions of the 'ideal man'. He devised a ratio between weight and height, originally termed the Quételet Index, and today widely known and used as the body mass index or BMI. In 1835, he demonstrated that a normal curve accommodates the distribution of human traits articulating his reasoning on human variance around the average. Quételet's long-lasting legacy of the establishment of a simple measure to classify people's weight relative to an ideal for their height endures today with minor variations having dramatically influenced public health agendas. While being very useful, the limitations of the BMI are well known. Thus, revisiting the beyond BMI paradigm is a necessity in the era of precision medicine with morphofunctional assessment representing the way forward via incorporation of body composition and functionality appraisal. While healthcare systems were originally designed to address acute illnesses, today's demands require a radical rethinking together with an original reappraisal of our diagnosis and treatment approaches from a multidimensional perspective. Embracing new methodologies is the way forward to advance the field, gain a closer look at the underlying pathophysiology of excess weight, keep the spotlight on improving diagnostic performance and demonstrate its clinical validity. In order to provide every patient with the most accurate diagnosis together with the most appropriate management, a high degree of standardization and personalization is needed.
- 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.
- 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.
- 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.
- 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.