Hepatic Glucocorticoid Receptor Plays a Greater Role Than Adipose GR in Metabolic Syndrome Despite Renal Compensation
Presentation Number: MON 377
Date of Presentation: April 3rd, 2017
Sandip Bose*1, Irina Hutson2 and Charles Andrew Harris2
1Washington University, St. Louis, MO, 2Washington University, St Louis, MO
Exogenous glucocorticoid (GC) administration results in hyperglycemia, insulin resistance, hepatic dyslipidemia and hypertension, a constellation of findings known as Cushing's syndrome. These effects are mediated by the glucocorticoid receptor (GR). Since GR activation in liver and adipose has been implicated in metabolic syndrome we wanted to determine the role of GR in these tissues in the development of metabolic syndrome. Since GRKO mice (whole body KO) exhibit perinatal lethality due to respiratory failure, we generated tissue specific (liver or adipose) GRKO mice using cre-lox technology. Real time PCR analysis of liver mRNA from dexamethasone treated WT and liver GRKO (LGRKO) mice indicated that hepatic GR regulates the expression of key genes involved in gluconeogenesis and glycogen metabolism. Interestingly, we have observed that liver specific deletion of GR resulted in a significant increase in mRNA expression of key genes involved in gluconeogenesis and glycogen metabolism in kidney tissue, indicating a compensatory mechanism to maintain glucose homeostasis. We have also observed that GR plays an important role in regulating the mRNA expression of key genes involved in lipid metabolism. LGRKO mice demonstrated decreased fat mass and liver glycogen content compared to WT mice administered dexamethasone for 2 weeks. Adipose specific deletion of GR did not alter glucose tolerance or insulin sensitivity of adipose GRKO (FGRKO) mice compared to WT mice administrated dexamethasone. This indicates that liver GR might be more important in development of metabolic syndrome in dexamethasone treated mice, while adipose GR plays a little role in these paradigms. However, deletion of GR in either of these tissues alone, likely results in a homeostatic compensatory program. We identified the kidney as a key component compensating for the absence of hepatic GR. These findings have significant clinical implications as it relates to the development of selective GR modulators for the treatment of metabolic disease.
Nothing to Disclose: SB, IH, CAH