糖皮质激素类药物在临床上具有广泛应用，但长期使用会引起糖尿病、高血压、脂肪肝和向心性肥胖等多种副作用，进而影响其在临床中的应用。已有报道表明，糖皮质激素能够促进肝脏糖异生基因的表达，并且抑制脂肪UCP1的表达。糖皮质激素引起肝脏糖异生和抑制UCP1的表达机制尚不明确。我们的前期研究发现糖皮质激素能明显促进肝脏和巨噬细胞Klf9（Krüppel-like factor 9）的mRNA和蛋白水平。为了探究Klf9在糖皮质激素发挥功能中的作用，我们使用小鼠原代肝脏细胞、巨噬细胞原代细胞，肝脏Klf9特异敲除小鼠、巨噬细胞Klf9特异敲除小鼠、C57BL/6J小鼠和db/db糖尿病小鼠模型，运用多种研究手段对Klf9进行过表达和敲低，并结合Western blot，RT-PCR，双荧光报告基因，染色质免疫共沉淀等多种研究技术，研究糖皮质激素与Klf9在机体代谢中的作用机制。肝脏作为机体重要的代谢器官，我们首先探索了糖皮质激素在肝脏发挥的作用，通过RNA-Seq、染色质免疫沉淀、双荧光报告基因等实验，发现Klf9在糖皮质激素促进糖异生的过程中发挥了重要作用。在细胞水平，使用腺病毒在小鼠肝脏原代细胞过表达Klf9能促进PGC-1α等糖异生基因表达上调，同时细胞葡萄糖输出增加。相反敲低Klf9可以明显削弱地塞米松对原代肝细胞葡萄糖输出的刺激作用。为了探究糖皮质激素药物通过Klf9激活肝脏糖异生的分子机制，通过尾静脉注射腺病毒在小鼠肝脏过量表达Klf9，发现肝脏过量表达Klf9能够引起高血糖症，并且促进PGC-1α等糖异生基因的表达。为了进一步验证Klf9促进糖异生过程，我们引进了肝脏特异Klf9基因敲除小鼠，发现肝脏特异Klf9基因敲除小鼠均表现出饥饿后低血糖的表型。而且，长期注射地塞米松不会导致肝脏特异Klf9基因敲除小鼠出现高血糖症；同时，地塞米松对PGC-1α等糖异生基因的促进作用在肝脏特异Klf9基因敲除小鼠中得到了明显抑制。这些结果表明Klf9在肝脏糖异生以及糖皮质激素诱导肝脏的糖异生过程中起着关键作用。其次，糖皮质激素在机体内发挥免疫抑制作用，所以我们接下来就研究了糖皮质激素对巨噬细胞的影响。结合细胞实验和动物实验，发现糖皮质激素能促进巨噬细胞Klf9表达增加。机体巨噬细胞Klf9过表达能够引起脂肪含量增加，抑制机体能量代谢。同时，巨噬细胞Klf9敲除能够改善糖皮质激素引起的体脂含量增多，同时还能抵抗高脂饮食引起的肥胖。我们的研究结果表明Klf9在糖皮质激素促进肝脏糖异生，影响脂肪细胞产热过程中发挥重要作用，为治疗糖皮质激素药物引起的糖尿病具有很好的临床应用价值。

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 (Krüppel-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-1α 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-1α. 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-1α 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.