Glucocorticoids Promote Gluconeogenesis And Obesity Via Klf9

Glucocorticoids are widely used in clinical practice,but long-term use can cause numerous side effects such as diabetes,hypertension,fatty liver,and concentric obesity,which will affect its clinical application.It has been reported that glucocorticoids can promote the expression of gluconeogenesis genes in the liver and inhibit the thermogenesis.The mechanism by which glucocorticoids cause gluconeogenesis of the liver and inhibit the thermogenesis is unclear.Our previous research revealed that glucocorticoids can significantly promote the mRNA and protein levels of Klf9(Kruppel-like factor 9)in liver and macrophages.However,the molecular mechanism of glucocorticoids and Klf9 in metabolism remains unclear.In this study,we use mouse primary liver cells,primary macrophage cells,liver-specific Klf9-deleted mice,macrophage-specific Klf9-deleted mice,C57BL/6J mice,and db/db diabetic mouse models to study the role of glucocorticoids and Klf9 in body metabolism.Combine with Multiple research methods such as Western blot,Real-time PCR,dual fluorescence report experiment and chromatin immunoprecipitation experiment to study the function of Klf9.The liver is an important metabolic organ of the body.We first explored the role of glucocorticoids in the liver.we found that Klf9 has a role in glucocorticoids promoting gluconeogenesis through RNA-Seq,chromatin immunoprecipitation,and dual fluorescent reporter genes.At the cellular level,we use adenovirus to overexpress Klf9 in mouse liver primary cells.We found Klf9 can promote gluconeogenic genes such as PGC-1? and increase glucose output.Conversely,knocking down Klf9 can significantly weaken dexamethasone's effect on the primary hepatocyte glucose output.To further explore the molecular mechanism of glucocorticoid activation of gluconeogenesis in the liver adenovirus was delivered intravenously.It was found that over-expression of Klf9 in the liver can cause hyperglycemia and promote the expression of gluconeogenic genes such as PGC-1?.To further verify that Klf9 promotes the gluconeogenesis process.We introduced liver-specific Klf9-deleted mice.We found that liver-specific Klf9-deleted mice display fasting hypoglycemia.Moreover,long-term injection of dexamethasone does not cause hyperglycemia in liver-specific Klf9-deleted mice.At the same time,the promotion effect of dexamethasone on gluconeogenic genes such as PGC-1? was significantly suppressed in liver-specific Klf9 gene knockout mice.These results indicate that Klf9 plays a critical role in liver gluconeogenesis.Second,glucocorticoids have immunosuppressive effects,so we next investigated the effects of glucocorticoids on macrophages.We found that glucocorticoids can promote macrophages Klf9 expression in vivo and in vitro.Overexpression of Klf9 in macrophages can increase fat content and inhibit energy metabolism.At the same time,myeloid-specific Klf9 deficiency in mice can improve adiposity caused by glucocorticoids,and alleviates obesity caused by high-fat diets.Our results show that Klf9 plays an important role in the process of glucocorticoids promoting liver gluconeogenesis and affecting the thermogenesis.These findings indicate that Klf9 has good clinical application value for the treatment of diabetes caused by glucocorticoid drugs.