1950-P: Effects of Dietary Composition on Intestinal Glucocorticoid Receptor Signaling

Enhanced glucose transport capacity of the intestinal epithelium, specifically enterocytes, is known to significantly contribute to systemic glucocorticoid (GC) - induced hyperglycemia. This effect is mainly dependent on overexpression of sodium glucose transporter 1 (Sglt1) and its enhanced activation by serum and glucocorticoid-regulated kinase 1 (Sgk1). In this work we aimed to investigate whether dietary intake affects intestinal glucocorticoid receptor (Nr3c1) signaling. In male C57/BL6 mice short term feeding of a Western diet (WD) resulted in increased glucocorticoid receptor expression in the ileum which was accompanied by an upregulation of the effector genes Sgk1 and sodium-hydrogen exchanger 3 (Nhe3) and liver receptor homologe 1 (Lrh1). The latter is known as the key regulator of intestinal corticosterone synthesis. Histological analysis showed that glucocorticoid receptor expression was mainly located in enterocytes. Intestinal Sgk1 expression remained significantly, about 2-fold, increased in mice fed a Western diet for 10 weeks, while Nr3c1, Lrh1 and Nhe3 expression levels were not significantly altered after long-term feeding. Further regulatory mechanisms were investigated in immortalized murine small intestine enterocyte cell line Mode-K: Stimulation with palmitic acid resulted in a significant upregulation of Sgk1 expression, while no effect was seen when exposed to oleic acid, arachidonic acid or docosahexanoic acid. In contrast to Sgk1, Nr3c1 expression was downregulated in Mode-K cells exposed to palmitic acid.

In conclusion, our data suggest that dietary fat intake might contribute to GC induced hyperglycemia by modulating intestinal Sgk1 expression in a glucocorticoid receptor-independent way.