Visceral adipose tissue and leptin increase colonic epithelial tight junction permeabilityviaa RhoA‐ROCK‐dependent pathway

Abstract

Proinflammatory cytokines produced by immune cells play a central role in the increased intestinal epithelial permeability during inflammation. Expansion of visceral adipose tissue (VAT) is currently considered a consequence of intestinal inflammation. Whether VAT per se plays a role in early modifications of intestinal barrier remains unknown. The aim of this study was to demonstrate the direct role of adipocytes in regulating paracellular permeability of colonic epithelial cells (CECs). We show in adult rats born with intrauterine growth retardation, a model of VAT hypertrophy, and in rats with VAT graft on the colon, that colonic permeability was increased without any inflammation. This effect was associated with altered expression of tight junction (TJ) proteins occludin and ZO-1. In coculture experiments, adipocytes decreased transepithelial resistance (TER) of Caco-2 CECs and induced a disorganization of ZO-1 on TJs. Intraperitoneal administration of leptin to lean rats increased colonic epithelial permeability and altered ZO-1 expression and organization. Treatment of HT29-19A CECs with leptin, but not adiponectin, dose-dependently decreased TER and altered TJ and F-actin cytoskeleton organization through a RhoA-ROCK-dependent pathway. Our data show that adipocytes and leptin directly alter TJ function in CECs and suggest that VAT could impair colonic epithelial barrier.

Circulating Biomarkers of Gut Barrier Function: Correlates and Nonresponse to Calcium Supplementation among Colon Adenoma Patients

“…For example, mice with induced metabolic endotoxemia (through infusion of LPS) experienced weight gain in 4 weeks, suggesting that the LPS system may trigger the onset of obesity (34). Conversely, mice with induced-obesity had significantly higher IgG against bacterial extracts (29), and rats with transplanted visceral adipose tissue or that were injected with leptin had increased colonic epithelial permeability as measured by expression of trans-epithelial resistance and tight junction proteins, suggesting that obesity may induce gut barrier impairment (35). In humans, plasma LPS levels were higher in obese individuals (n = 49) than in controls (n = 17), but they were reduced after bariatric surgery; however, reduced LPS levels were not found with a preoperative weight-loss intervention, and the postoperative LPS reduction was not correlated with a BMI reduction, suggesting mechanisms beyond weight loss (36).…”

Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine

“…Furthermore, along with increased leptin level in serum we also observed increased expression of leptin receptors and activation of Jak2/Stat3 signaling, which is downstream of leptin, in intestine as well as in colon. Importantly, the Jak2/Stat3 pathway is involved in cellular growth and differentiation and is implicated in intestinal homeostasis as well as in colorectal carcinogenesis656667. Specifically, Jak2/Stat3 along with RhoA/ROCK and AMPK pathways, which are downstream to leptin, due to their roles in cellular tight junctions (TJ) could adversely influence intestinal epithelial cell migration as well as intestinal epithelial barrier6667.…”

“…Importantly, the Jak2/Stat3 pathway is involved in cellular growth and differentiation and is implicated in intestinal homeostasis as well as in colorectal carcinogenesis656667. Specifically, Jak2/Stat3 along with RhoA/ROCK and AMPK pathways, which are downstream to leptin, due to their roles in cellular tight junctions (TJ) could adversely influence intestinal epithelial cell migration as well as intestinal epithelial barrier6667. Although we have shown long-term activation of leptin signaling, additional experiments will be required to understand its impact on metabolic functions such as regulation of energy expenditure and glucose metabolism2466.…”

Synthesis and evaluation of the structural elements in alkylated tetrahydroisoquinolines for binding to CNS receptors

“…This is of biological significance because of the paucity of selective dual 5-HT 1A and 5-HT 7 receptor ligands in the literature. 24 Also, a growing body of knowledge suggests that the 5-HT 7 receptor controls normal circadian rhythm, sleep, mood, memory and learning, and cognition 25-27 and may therefore serve as a plausible target for treating neuropsychiatric disorders such as schizophrenia and mood disorders. Having obtained 3h as a possible lead, we investigated the effect of removing the fluoro group in 3h to produce compound 3i .…”