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。在骨髓中，MSCs向脂肪细胞或成骨细胞的分化是竞争性平衡的；促进一个细胞命运的机制积极抑制诱导另一种血统的机制。糖皮质激素(GCs)在临床上被用于治疗各种免疫介导性疾病，但其长期使用与多种代谢副作用有关，包括骨质疏松和肥胖。然而，内源性糖皮质激素在代谢和能量平衡中的作用尚未完全阐明，内源性糖皮质激素是在ACTH的排他性调节下在肾上腺皮质合成的。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MC2R^&lt；-/-&gt；和CRH^&lt；-/-&gt；小鼠作为慢性肾上腺皮质功能不全的模型。MC2R^&lt；-/-&gt；小鼠在老年时身体较瘦，脂肪量减少。MC2R^&lt；-/-&gt；小鼠的脂肪组织重量减轻，而附睾白脂肪组织中脂肪细胞的大小与MC2R^&lt；-/-&gt；小鼠相当，表明MC2R^&lt；-/-&gt；小鼠的白色脂肪细胞数量比MC2R^&lt；+/-&gt；小鼠减少。MC2R^&lt；-/-&gt；和CRH^&lt；-/-&gt；小鼠对高脂饮食诱导的肥胖和胰岛素抵抗都有抵抗力，并且它们在老年时都表现出高骨量表型。我们的结果与糖皮质激素在MSCs向脂肪细胞或成骨细胞分化中的作用是一致的，即阻止成骨分化和促进成脂分化。

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.