Liraglutide modulates morpho-functional and inflammatory gastrointestinal responses in rats.

BACKGROUND: Obesity impairs homeostatic control of energy and is associated with chronic low-grade inflammation. Effects of glucagon-like peptide-1, the target in the gastrointestinal tract for anti-obesity drugs such as Liraglutide, were not properly associated with inflammation markers. This study investigated the effects of Liraglutide on metabolic and gastrointestinal parameters in a rat model of obesity. METHODS: Twenty-six Wistar rats with obesity were randomly distributed to receive saline (n = 10), 400 µg (n = 8), or 1200 µg of Liraglutide/kg/day (n = 8), subcutaneously for 30 consecutive days, once a day. Weight gain, feeding efficiency, caloric consumption, gastric motility, adiposity, histomorphometric, murinometric, biochemical parameters and cytokines TNF-α and TGF-ß1 in duodenal tissue were measured. Data were analysed by ANOVA, followed by Bonferroni post hoc or Kruskal-Wallis test, followed by Dunn's multiple comparison test. RESULTS: Liraglutide-treated animals had better feeding efficiency and higher caloric intake in a dose-dependent manner. Higher doses slowed gastric emptying and diminished the amplitude of gastric contractions. These effects were accompanied by decreases in intestinal muscle layer thickness and crypt depth. Liraglutide significantly reduced retroperitoneal and visceral white adipose tissue depots. High-dose treatment decreased levels of TNF-α and enhanced levels of TGF-ß1 in duodenal tissue. Liraglutide treatment provided significant reductions in total cholesterol, triglyceride and hepatic transaminases. CONCLUSIONS: Liraglutide reduced fat accumulation, improved metabolic parameters and downregulated levels of inflammatory signalling in duodenal tissue. Liraglutide at high doses controlled obesity-related outcomes, and such effects seemed to be driven by its action on glucagon-like peptide-1 receptors in the gastrointestinal tract slowing gastric motility.

Alternate-day fasting induces metabolic and morphofunctional changes in the gastrointestinal tract of male rats.

Alternate-day fasting (ADF) is a nutritional intervention with modulatory and overall protective effects, but its role in the gastrointestinal (GI) tract is still uncertain. The aim of this study was to investigate the influence of ADF on the metabolic patterns and morphofunctional motility of the GI tract in rats. Thirty-two male Wistar rats were allocated into groups: control for 15 days (CON 15, n = 8), control for 30 days (CON 30, n = 8), ADF for 15 days (ADF 15, n = 8), and ADF for 30 days (ADF 30, n = 8). Blood glucose, body weight, and food and water consumption were measured. Frequency and amplitude of gastric contractions as well as gastric emptying time, small intestinal transit time, and cecum arrival time were measured. Intestinal histomorphometric, relative weight of organs, lipidogram, and leptin levels were also evaluated. ADF decreased water consumption and food consumption. The weight gain decreased; however, the relative kidney weight increased. ADF triggered an increase in the amplitude of gastric contractions and accelerated gastric emptying. However, small intestinal transit time was delayed in both ADF groups. Total cholesterol, triglycerides, non-HDL cholesterol, and very low-density lipoprotein cholesterol levels decreased, whereas villus height, depth of the crypts and thickness of the circular, and longitudinal muscular layers of intestine increased after ADF. In conclusion, our results showed ADF exert an effect on both metabolism and GI motility and impacts on overall digestive functions.

BALB/c and C57BL/6 mouse strains influence gastric function outcomes with administration of cisplatin and dexamethasone

Abstract Our aim was to evaluate the effects of cisplatin and dexamethasone alone and combined on gastric contractility and histomorphometry of BALB/c and C57BL/6 mice. BALB/c and C57BL/6 male mice (8-week-old) were randomly separated into: Control; Cisplatin (7.5 mg/Kg); Dexamethasone (2.0 mg/Kg); and Dexamethasone plus Cisplatin (2.0 mg/Kg of dexamethasone 1-hour prior to 7.5 mg/Kg of cisplatin). Drugs were administered intraperitoneally for three days. Body weight and food intake were evaluated on 2nd day. Alternating Current Biosusceptometry technique was employed to measure gastric contractions on 3rd day. Afterward, mice were killed for gastric histomorphometric analysis. Cisplatin decreased food intake and caused bradygastria in BALB/c mice; however, the amplitude of gastric contractions decreased in both BALB/c and C57BL/6. Dexamethasone and cisplatin combined restored the gastric frequency and food intake only in BALB/c, but drug combination reduced the gastric amplitude of contractions in both strains. Dexamethasone alone increased gastric mucosa thickness in C57BL/6 and decreased muscular thickness in BALB/c. In conclusion, the mouse strains presented differences in acute effects of cisplatin and dexamethasone alone and combined on gastric function. This reinforces the importance of choosing the appropriate mouse strain for studying the acute effects of drugs on the gastrointestinal tract.

Comparison of ketamine-xylazine and ketamine-dexmedetomidine anesthesia and intraperitoneal tolerance in rats.

We compared ketamine-xylazine (K, 100 mg/kg; X, 10 mg/kg) and ketamine-dexmedetomidine (K, 75 mg/kg; D, 1.0 mg/kg) for their ability to produce anesthesia, their tissue tolerance, and the reversibility of their effects by atipamezole (1.0 mg/kg) after intraperitoneal administration to Wistar Han rats. Both anesthetic combinations led to a comparable level of anesthesia over a 30-min period. However, the administration of KD led to a 20% decrease in heart rate, 33% decrease in respiratory rate, and a 20% decrease in peripheral oxygen saturation from baseline levels. Intraperitoneal administration of saline and both anesthetic combinations was associated with mild transient increases in serum ALT and AST concentrations in the absence of histomorphologic findings in liver. Muscle and tissue necrosis at the intraperitoneal injection sites correlated with increases in serum creatine kinase concentrations in rats given KD or KX; these increases were more severe in the KX group than the KD group. Compared with KX, intraperitoneal administration of KD offered better local tolerance and anesthesia of similar quality and depth.

GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals.

Inflammasomes are sensory complexes that alert the immune system to the presence of infection or tissue damage. These complexes assemble NLR (nucleotide binding and oligomerization, leucine-rich repeat) or ALR (absent in melanoma 2-like receptor) proteins to activate caspase-1 cleavage and interleukin (IL)-1ß/IL-18 secretion. Here, we identified a non-NLR/ALR human protein that stimulates inflammasome assembly: guanylate binding protein 5 (GBP5). GBP5 promoted selective NLRP3 inflammasome responses to pathogenic bacteria and soluble but not crystalline inflammasome priming agents. Generation of Gbp5(-/-) mice revealed pronounced caspase-1 and IL-1ß/IL-18 cleavage defects in vitro and impaired host defense and Nlrp3-dependent inflammatory responses in vivo. Thus, GBP5 serves as a unique rheostat for NLRP3 inflammasome activation and extends our understanding of the inflammasome complex beyond its core machinery.