Sex differences and effects of oestrogen in rat gastric mucosal defence

AIM To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence.METHODS Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry.RESULTS The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 ± 0.12 m L/min·g in males and 0.51 ± 0.03 m L/min·g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 ± 1 μm and 80 ± 3 μm respectively. After 60 min the mucus thickness increased to 113 ± 3 μm in males and 121 ± 3 μm in females with no statistically significant difference seen between the sexes. Following oestrogen administration(0.1 followed by 1 μg/kg·min), mean blood flow in the gastric mucosa decreased by 31% [68 ± 13 perfusion units (PFU)] in males which was significantly different compared to baseline(P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 ± 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 ± 0.04 to 1.1 ± 0.1 m L/min·100 g in males and 0.4 ± 0.3 to 2.1 ± 0.3 m L/min·100 g in females(P = 0.065)]. There were no significant differences between 17β-Estradiol treated males (mean ratio of positive staining ± SEM)(0.06 ± 0.07) and females(0.11 ± 0.11) in the staining of ERα (P = 0.24). Also, there were no significant differences between 17β-Estradiol treated males (0.18 ± 0.21) and females (0.06 ± 0.12) in the staining of ERβ (P = 0.11). Finally, there were no significant differences between 17β-Estradiol treated males (0.04 ± 0.05) and females (0.11 ± 0.10) in the staining of CGRP(P = 0.14).CONCLUSION Gastric mucosal blood flow is higher in male than in female rats and is reduced in male rats by oestrogen administration.

The Liver X-Receptor (Lxr) Governs Lipid Homeostasis in Zebrafish during Development

The liver X-receptors (LXRs) act as cholesterol sensors and participate in the regulation of lipid and cholesterol metabolism. The objective of this study was to determine the role of LXR during development using the zebrafish model. By in situ hybridization we showed distinct expression of lxr in the brain and the retina in the developing and adult zebrafish. Lxr ligand activation affected the expression of genes involved in lipid metabolism in zebrafish adult brain and eye as well as in zebrafish embryos. Morpholino knock down of lxr resulted in an overall impaired lipid deposition as determined by oil red O staining particularly in the head and around the eyes, and to significantly elevated levels of both total and free cholesterol in the yolk of lxr morphant embryos. The expression of genes involved in lipid and cholesterol metabolism was also changed in the lxr morphants. Furthermore, alcian blue staining revealed malformation of the pharyngeal skeleton in the lxr morphant. Our data show that lxr is an important component of the regulatory network governing the lipid homeostasis during zebrafish development, which in turn may support a role of lxr for normal development of the central nervous sytem, including the retina.

Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue

Among the four prostaglandin E2 receptors,EP3 receptor is the one most abundantly expressed in white adipose tissue(WAT).The mouse EP3 gene gives rise to three isoforms,namely EP3α,EP3β,and EP3γ,which differ only at their C-terminal tails.To date,functions of EP3 receptor and its isoforms in WAT remain incompletely characterized.In this study,we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice.Genetic ablation of three EP3 receptor isoforms(EP3^(−/−)mice)or EP3αand EP3γisoforms with EP3βintact(EP3βmice)led to an obese phenotype with increased food intake,decreased motor activity,reduced insulin sensitivity,and elevated serum triglycerides.Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγpathway,increased adipogenesis may contribute to obesity in EP3^(−/−)and EP3βmice.Moreover,both EP3^(−/−)and EP3βmice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway.Taken together,our findings suggest that EP3 receptor and itsαandγisoforms are involved in both adipogenesis and lipolysis and influence food intake,serum lipid levels,and insulin sensitivity.