Tratamento com liraglutida in vitro e in vivo: efeitos celulares, na motilidade e na resposta inflamatória de tecido epitelial intestinal de ratos

Abstract

Obesity is a chronic disease, characterized by a state of low-grade inflammation, which affects gastrointestinal permeability and motility, and the action of cytokines in this scenario is little reported. Liraglutide is an analogue of glucagon-like peptide-1 (GLP-1) that induces weight loss by different mechanisms involving the gastrointestinal tract. The objective of this study is to evaluate the effects of Liraglutide on intestinal epithelial cells in vitro and on metabolic, morpho-functional and inflammatory parameters in the gastrointestinal tract of obese rats. Methods: In the in vitro assay, IEC6 cells were treated with concentrations of 0.25 to 100 µM of Liraglutide and evaluated for cell viability, cell death by apoptosis and necrosis, morphological analysis, actin cytoskeletal reorganization and assay of cell migration for wound healing. In the in vivo assay, obese Wistar rats were randomly assigned to receive saline solution, 400 or 1200 µg Liraglutide/kg/day subcutaneously for 30 consecutive days, once a day. Weight gain, feed efficiency, caloric intake, gastric motility, adiposity, histomorphometric, murinometric, and biochemical parameters were evaluated before and after treatment. Results: There was no change in the viability of cells treated with Liraglutide at concentrations of 0.25, 0.5 and 1 μM; moreover, drug treatment decreased the rate of apoptosis of IEC-6 cells relative to control. Treated cells showed a modified actin cytoskeleton, with prominent stress fibers and decreased cell migration. The effects of Liraglutide in treated animals were dose dependent. The dose of 1200 µg/day/kg provided lower weight gain, lower feed efficiency and lower caloric intake, with slower gastric emptying and lower amplitude of gastric contractions. Gastrointestinal effects were accompanied by reductions in muscle layer thickness and crypt depth. Liraglutide reduced retroperitoneal and visceral adipose tissue deposits, decreased TNF-α levels, and increased TGF-β1 levels. There was a reduction in total cholesterol, triglycerides and liver transaminases. Conclusion: Liraglutide directly affected intestinal cells, decreasing the rate of apoptosis, the disposition of the actin cytoskeleton, reducing cell migration. In rats, it reduced fat accumulation, improved metabolic parameters, and minimized the expression of inflammatory signaling in the gastrointestinal tract.