Martín-Rodríguez, M. (Marina)
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- Effect of guanylin peptides on pancreas steatosis and function in experimental diet-induced obesity and after bariatric surgery(2023) Valenti, V. (Víctor); Otero, A. (Aarón); Catalan, V. (Victoria); Álvarez-Cienfuegos, J. (Javier); Becerril, S. (Sara); Frühbeck, G. (Gema); Burrell, M.A. (María Ángela); Martín-Rodríguez, M. (Marina); Gomez-Ambrosi, J. (Javier); Rodriguez, A. (Amaia); Moncada-Durruti, R. (Rafael)Introduction: Obesity contributes to ectopic fat deposition in non-adipose organs, including the pancreas. Pancreas steatosis associates with inflammation and beta-cell dysfunction, contributing to the onset of insulin resistance and type 2 diabetes. An improvement of pancreatic steatosis and indices of insulin resistance is observed following bariatric surgery, but the underlying mechanisms remain unknown. We sought to analyze whether guanylin (GUCA2A) and uroguanylin (GUCA2B), two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of pancreas fat accumulation after bariatric surgery. Methods: Pancreas steatosis, inflammation, islet number and area were measured in male Wistar rats with diet-induced obesity (n=125) subjected to surgical (sham operation and sleeve gastrectomy) or dietary (pair-fed to the amount of food eaten by gastrectomized animals) interventions. The tissue distribution of guanylate cyclase C (GUCY2C) and the expression of the guanylin system were evaluated in rat pancreata by real-time PCR, Western-blot and immunohistochemistry. The effect of guanylin and uroguanylin on factors involved in insulin secretion and lipogenesis was determined in vitro in RIN-m5F beta-cells exposed to lipotoxic conditions. Results: Sleeve gastrectomy reduced pancreas steatosis and inflammation and improved insulin sensitivity and synthesis. An upregulation of GUCA2A and GUCY2C, but not GUCA2B, was observed in pancreata from rats with dietinduced obesity one month after sleeve gastrectomy. Interestingly, both guanylin and uroguanylin diminished the lipotoxicity in palmitate-treated RIN-m5F beta-cells, evidenced by lower steatosis and downregulated lipogenic factors Srebf1, Mogat2 and Dgat1. Both guanylin peptides reduced insulin synthesis (Ins1 and Ins2) and release from RIN-m5F beta-cells, but only guanylin upregulated Wnt4, a factor that controls beta-cell proliferation and function. Discussion: Together, sleeve gastrectomy reduced pancreatic steatosis and improved beta-cell function. Several mechanisms, including the modulation of inflammation and lipogenesis as well as the upregulation of GUCA2A in the pancreas, might explain this beneficial effect of bariatric surgery.
- Uroguanylin prevents hepatic steatosis, mitochondrial dysfunction and fibrosis in obesity-associated NAFLD(Elsevier, 2023) Fernández-Sáez, E.M. (Eva M.); Losarcos, M. (Maite); Becerril, S. (Sara); Valenti, V. (Víctor); Moncada, R. (Rafael); Martín-Rodríguez, M. (Marina); Burrell, M.A. (María Ángela); Catalan, V. (Victoria); Gomez-Ambrosi, J. (Javier); Mugueta, C. (Carmen); Colina, I. (Inmaculada); Escalada, J. (Javier); Frühbeck, G. (Gema); Rodriguez, A. (Amaia)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.
- Enseñando Biología III(Servicio de Publicaciones de la Universidad de Navarra, 2018) Ibañez-Gaston, R. (Ricardo); González-Fernández, D. (David); Galicia-Paredes, D. (David); Fernández-Rodríguez, J. (Juana); Izal-Azcárate, I. (Íñigo); Martín-Rodríguez, M. (Marina); Bodegas-Frías, E. (Elena)