Effect of guanylin peptides on pancreas steatosis and function in experimental diet-induced obesity and after bariatric surgery

Frontiers in Endocrinology

Endocrinology

Rafael Moncada¹  María A. Burrell²  Javier A. Cienfuegos³  Víctor Valentí³  Marina Martín⁴  Aarón Otero⁵  Victoria Catalán⁶  Amaia Rodríguez⁶  Javier Gómez-Ambrosi⁶  Sara Becerril⁶  Gema Frühbeck⁷ 

[1] CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain;Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain;Department of Anesthesia, Clínica Universidad de Navarra, Pamplona, Spain;CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain;Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain;Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain;CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain;Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain;Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain;Department of Pathology, Anatomy and Physiology, University of Navarra, Pamplona, Spain;Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain;Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain;CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain;Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain;Metabolic Research Laboratory, Clínica Universidad de Navarra, Pamplona, Spain;CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain;Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain;Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain;

关键词: uroguanylin;    guanylin;    guanylate cyclase 2C;    β-cell function;    lipogenesis;   

DOI  :  10.3389/fendo.2023.1185456

 received in 2023-03-13, accepted in 2023-05-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionObesity contributes to ectopic fat deposition in non-adipose organs, including the pancreas. Pancreas steatosis associates with inflammation and β-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.MethodsPancreas 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 β-cells exposed to lipotoxic conditions.ResultsSleeve 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 diet-induced obesity one month after sleeve gastrectomy. Interestingly, both guanylin and uroguanylin diminished the lipotoxicity in palmitate-treated RIN-m5F β-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 β-cells, but only guanylin upregulated Wnt4, a factor that controls β-cell proliferation and function.DiscussionTogether, sleeve gastrectomy reduced pancreatic steatosis and improved β-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.

【 授权许可】

Unknown   
Copyright © 2023 Otero, Becerril, Martín, Cienfuegos, Valentí, Moncada, Catalán, Gómez-Ambrosi, Burrell, Frühbeck and Rodríguez