The analysis of ACTH receptor deficient mice

骨髓间充质干细胞（MSCs）是一种多能细胞，可分化为脂肪细胞和成骨细胞。在骨髓内，MSC分化成脂肪细胞或成骨细胞是竞争性平衡的;促进一种细胞命运的机制积极抑制诱导替代谱系的机制。糖皮质激素（GC）在临床上用于治疗多种免疫介导的疾病，但其长期施用与多种代谢副作用相关，包括骨质疏松症和肥胖症。然而，内源性糖皮质激素的作用，这是合成的肾上腺皮质下的独家调节ACTH，在代谢和能量平衡没有完全阐明。为了分析内源性糖皮质激素在代谢和能量平衡中的作用，我们分析了作为慢性肾上腺功能不全模型的MC 2 R ^<-/->和CRH^<-/->小鼠。MC 2 R ^<-/->小鼠在老年时具有瘦体和减少的脂肪量。在MC 2 R ^<-/->小鼠中脂肪组织重量减少，而在MC 2 R ^<-/->小鼠和MC 2 R ^<+/->对照之间附睾白色脂肪组织中的脂肪细胞大小相当，表明与MC 2 R ^<+/->对照相比，MC 2 R ^<-/->小鼠中白色脂肪细胞数量减少。MC 2 R ^<-/->和CRH^<-/->小鼠均对高脂饮食诱导的肥胖和胰岛素抵抗具有抵抗性，并且它们在老年时表现出高骨量表型。我们的研究结果与糖皮质激素在MSC分化为脂肪细胞或成骨细胞中的作用一致，即阻断成骨分化并促进成脂分化。

Bone marrow mesenchymal stem cells (MSCs) are multipotent cells, which give rise to adipocytes and osteoblasts. Within the bone marrow, the differentiation of MSCs into adipocytes or osteoblasts is competitively balanced; mechanisms that promote one cell fate actively suppress mechanisms that induce the alternative lineage. Glucocorticoids (GCs) are used clinically in many situations to treat various immune-mediated diseases, but their long-term administration is associated with multiple metabolic side effects, including osteoporosis and obesity. However, the role of endogenous glucocorticoid, which is synthesized in the adrenal cortex under the exclusive regulation of ACTH, in metabolism and energy balance is not fully elucidated. To analyze the role of endogenous glucocorticoid in metabolism and energy balance, we analyzed MC2R^<-/-> and CRH^<-/-> mice as models of chronic adrenal insufficiency. MC2R^<-/-> mice had lean bodies in old age and reduced fat mass. Adipose tissue weight was decreased in MC2R^<-/-> mice, while adipocyte size in epididymal white adipose tissue were comparable between MC2R^<-/-> mice and MC2R^<+/-> controls, suggesting that white adipose cell number is decreased in MC2R^<-/-> mice compared to MC2R^<+/-> controls. Both MC2R^<-/-> and CRH^<-/-> mice were resistance to high-fat diet-induced obesity and insulin resistance, and they exhibited a high bone mass phenotype in old age. Our results are consistent with the proposed roles of glucocorticoid in the differentiation of MSCs into adipocytes or osteoblasts, i.e. blocks osteogenic differentiation and promotes adipogenic differentiation.