Endocrine Abstracts

Introduction: Overweight and obesity is a worldwide chronic disease affecting 2 billion adults and millions of children. In diet-induced obesity (DIO), current treatments are not always effective or suitable for all patients due to the complexity of obesity and its associated health complications. Recently, the potential of developing weight loss therapy by targeting the gut microbiota has been raised. Previously, we have shown that mice overexpressing insulin-like growth factor-1 receptor in the endothelium (hIGFREO) are protected against DIO and glucose intolerance, which is associated with remodelling of the gut microbiota (1). In vitro experiments suggested endothelium-enterocyte crosstalk may be involved in elevating Regenerating Family Member 3 Gamma (REG3G) signalling and remodelling of gut microbiota in hIGFREO mice (1).

Hypothesis: Elevated enterocyte REG3G signalling is mediated by secreted factors from endothelial cells in diet-challenged hIGFREO mice.

Methods: At 8 weeks old, hIGFREO and wild-type (WT) mice were challenged with high fat diet for 8 weeks. Conditioned media from isolated endothelial cells were applied on differentiated Caco-2 enterocytes. Aqueous and lipid fractions of conditioned media were extracted using methanol/chloroform mixture. Untargeted metabolomics was performed on the conditioned media using UPLC/MS.

Results: Aqueous fraction of hIGFREO endothelial cell-conditioned media induced a 3-fold increase in REG3G gene expression in Caco-2 enterocytes. Caco-2 enterocytes treated with either unconditioned media, aqueous or lipid fractions of WT endothelial cell-conditioned media showed no difference in REG3G gene expression. Untargeted metabolomics revealed 3 upregulated and 3 downregulated aqueous features in hIGFREO conditioned media compared to the WT control.

Conclusion: hIGFREO endothelial cells can secrete aqueous factors to increase enterocyte REG3G signalling in vitro. Future work will focus on annotating upregulated aqueous metabolites from hIGFREO endothelial cells and exploring their ability to alter REG3G signalling in enterocytes.

Reference: 1. Haywood NJ et al. EMBO Rep. 2021;22(5):e50767.