SAT-153 Role Of Increased Serum- And Glucocorticoid-inducible Kinase 1 (SGK1) Activity In Gluconeogenesis And Liver Metabolism During Metabolic Syndrome.

Abstract

SGK1 is a serine/threonine kinase expressed in different tissues included liver. At the cellular level, SGK1 expression is upregulated by multiple stimuli including gluco- and mineralo-corticoids, glucose and growth factors. Its activation depends on the PI3K pathway, playing a role in insulin sensitivity. To explore the functional role of SGK1 activity in liver metabolism during obesity and metabolic syndrome, we assessed the effects of a high fat diet (HFD) on transgenic mice expressing a constitutively active SGK1. During the first 6 weeks of HFD, we found that Tg.SGK1 mice were more prone to diet-induced weight gain compared to wild-type animals, despite a lower food intake. Metabolically, Tg.SGK1 displayed higher plasma and liver triglyceride levels and fatty liver was observed in these mice by week 6. Further metabolic disorders, such as a lower tolerance to glucose (glucose tolerance test, GTT) and a higher resistance to insulin (insulin tolerance test, ITT) were found in Tg.SGK1 fed a HFD. Significant high levels of blood pressure were also observed in Tg.SGK1 mice compared to Wt. We next tested whether the anti-hyperglycemic, insulin-sensitizing agent metformin was able to revert the observed phenotype. After 6 weeks of HFD animals were treated with 100 mg/kg/day of metformin for 12 weeks. Metformin produce a significant reduction in blood pressure in Tg.SGK1, but not in Wt mice. At week 3 Tg.SGK1 showed an improved response to insulin compared to Wt mice while glucose tolerance was also corrected at week 5. Mice were then challenged with a pyruvate tolerance test to measure gluconeogenesis. HFD-treated Tg.SGK1 mice showed poorer tolerance to pyruvate than Wt animals an effect that was reverted by metformin.This suggests that gluconeogenesis could be increased in Tg.SGK1 mice. Liver expression of glucose uptake and gluconeogenesis markers was analysed by real-time PCR. HFD induced high levels of Glut2 mRNA in Wt, but not in transgenic mice. Tg.SGK1 mice showed increased basal levels of G6Pc expression, which was suppressed after HFD. PCK1 expression was increased by HFD in both genotypes but to a lesser extent in Tg.SGK1 mice. Metformin treatment significantly increased G6PC and PCK1 expression levels in both genotypes, but both markers remained expressed at higher levels in Wt mice. Taken together, these data demonstrates that SGK1 plays a role in the development of metabolic disorders and associated hypertension. Furthermore, the data suggest that SGK1 may regulate gluconeogenesis in the liver.