Serotonin receptor type 3 antagonists improve obesity-associated fatty liver disease in mice

ABSTRACT Obesity is a major cause for nonalcoholic fatty liver disease (NAFLD). Previous studies suggested that alterations in intestinal motility and permeability contribute to the development of NAFLD. Serotonin and serotonin receptor type 3 (5-HT 3 R) are key factors in the regulation of intestinal motility and permeability. Therefore, we studied the effect of the 5-HT 3 R antagonists tropisetron and palonosetron on the development of NA-FLD in leptin-deficient obese mice. Four-week-old ob/ob mice and lean controls were treated for 6 weeks orally with tropisetron or palonosetron at 0.2 mg/kg per day. We determined markers of liver damage and inflammation, portal endotoxin levels, and duodenal concentrations of serotonin, serotoninreuptake transporter (SERT), occludin, and claudin-1. Tropisetron treatment significantly reduced liver fat content (Ϫ29%), liver inflammation (Ϫ56%), and liver cell necrosis (Ϫ59%) in ob/ob mice. The beneficial effects of tropisetron were accompanied by a decrease in plasma alanine aminotransferase and portal vein plasma endotoxin levels, an attenuation of enhanced MyD88 and tumor necrosis factor-␣ mRNA expression in the liver, and an increase of tight junction proteins in the duodenum. Tropisetron treatment also caused a reduction of elevated serotonin levels and an increase of SERT in the duodenum of ob/ob mice. Palonosetron had similar effects as tropisetron with regard to the reduction of liver fat and other parameters. Tropisetron and palonosetron are effective in attenuating NAFLD in a genetic mouse model of obesity. The effect involves the intestinal nervous system, resulting in a reduction of endotoxin influx into the liver and subsequently of liver inflammation and fat accumulation

The role of intestinal serotonergic system in the development of obesity and diet-induced non-alcoholic fatty liver disease in mice

Weltweit hat die Prävalenz von Übergewicht und Adipositas in den letzten Jahrzehnten dramatisch zugenommen. Die Ursachen, die zur Entwicklung von Adipositas beitragen, sind zahlreich und komplex. Gleiches trifft auch auf die Entwicklung der nicht-alkoholbedingten Fettlebererkrankung (NAFLD) zu, die mit Übergewicht und Adipositas assoziiert ist. Die Hypothese, dass zuckergesüßte Getränke zur Entwicklung von Adipositas und NAFLD beitragen, wurde durch verschiedene Tierstudien bereits nachgewiesen. Neuerdings werden Veränderungen auf der Ebene des Gastrointestinaltrakes als mögliche Faktoren, die sowohl zur Entwicklung von Adipositas als auch NAFLD beitragen, diskutiert. Von besonderer Bedeutung könnte hierbei das enterische Nervensystem (ENS) sein, das wichtige Darmfunktionen wie Peristaltik, Sekretion und Permeabilität über seinen Haupt-Neurotransmitter Serotonin (5-HT) und dessen verschiedenen Rezeptoren reguliert. Durch den 5-HT-Wiederaufnahme Transporter (SERT) wird die Bioverfügbarkeit des Serotonins reguliert. Ziel dieser Arbeit war es, zu untersuchen, welche Rolle das intestinale serotonerge System und dabei im speziellen SERT und der 5-HT3R in der Ausbildung der zuckerinduzierten Adipositas und NAFLD in verschiedenen Mausmodellen spielt.The worldwide prevalence of overweight and obesity has increased dramatically throughout the last decades. The causes of obesity are numerous and complex and the understanding of the mechanism(s) involved in the disease process are still limited. The same is true for the development of NAFLD, a liver disease for which a strong association with overweight and obesity has repeatedly been shown. High dietary fat intake has long been thought to be the major cause of obesity and NAFLD. However, other factors like carbohydrate intake may also contribute. Alterations at the level of the intestinal tract have also been discussed to be associated with the development of NAFLD and obesity. The enteric nervous system (ENS) might be of particular importance in this context, regulating the fundamental intestinal functions like peristalsis, secretion and permeability through its main neurotransmitter serotonin (5-HT) and different 5-HT receptors. The termination of the 5-HT action is mediated by the 5-HT selective reuptake transporter (SERT), located on epithelial cells. Based on this background the aim of the present work was to investigate the role of the intestinal serotonergic system and herein particularly of SERT and 5-HT3R in the onset of sugar-induced overweight and NAFLD as well as in the progression of NAFLD in mouse models

Estimating quantitative features of nanoparticles using multiple derivatives of scattering profiles

Due to copyright restrictions, the access to the full text of this article is only available via subscription.Characterization of nanoparticles on surfaces is a challenging in verse problem whose solution has many practical applications. This article proposes a method, suitable for in situ characterization systems, for estimating quantitative features of nanoparticles on surfaces from scattering profiles and their derivatives. Our method enjoys a number of advantages over competing approaches to this inverse problem. One such advantage is that only a partial solution is required for the companion direct problem. For example, estimating the average diameter of nanoparticles to be 53 nm is possible even when a researcher’s existing scattering data pertain to nanoparticles whose average diameters are in multiples of 5 nm. Two numerical studies illustrate the implementation and performance of our method for inferring nanoparticle diameters and agglomeration levels respectively.NS