Abnormal development of the central nervous system of the knockout mouse that becomes obese

类固醇生成因子1（SF-1）是一种孤儿核受体，在肾上腺和性腺发育、垂体促性腺激素表达和下丘脑腹内侧核（VMH）发育中起关键作用。如果通过肾上腺移植存活，SF-1敲除（KO）小鼠会出现代谢综合征，其特征为延迟性肥胖和运动活动减少，摄食量无变化。为了定义SF-1在VMH中的特定角色，我们使用Cre-loxP系统以CNS特定的方式来识别SF-1。使用nestin-Cre转基因，其在胚胎发生期间使SF-1失活，我们在很大程度上概括了在全球SF-1 KO小鼠中观察到的VMH结构缺陷。这些CNS特异性SF-1 KO小鼠的运动活动减少，并在高脂肪饮食下变得肥胖。在测量焦虑的行为测试中，他们比野生型的同窝仔明显更“焦虑”。此外，CNS特异性SF-1基因敲除小鼠VMH区域的脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）、促肾上腺皮质激素释放激素2型受体（corticotropin-releasing hormone，CRF-R_2）和瘦素受体（leptin receptor，Leptin receptor，Leptin receptor）等基因的表达明显降低。这些发现揭示了SF-1在体重和焦虑的关键调节因子的下丘脑表达中的重要作用，为SF-1的CNS特异性KO引起的表型提供了合理的分子解释。

Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that plays key roles in adrenal and gonadal development, expression of pituitary gonadotropins, and development of the ventromedial hypothalamic nucleus (VMH). If kept alive by adrenal transplantation, SF-1 knockout (KO) mice develop a metabolic syndrome characterized by delayed-onset obesity and decreased locomotor activity, with no change in food consumption. To define specific roles of SF-1 in the VMH, we used the Cre-loxP system to inactivate SF-1 in a CNS-specific manner. Using the nestin-Cre transgene, which inactivates SF-1 during embryogenesis, we largely recapitulated the VMH structural defect seen in the global SF-1 KO mice. These CNS-specific SF-1 KO mice had decreased locomotor activity and became obese on a high-fat diet. In behavioral tests felt to measure anxiety, they were significantly more "anxious" than wild-type littermates. In addition, CNS-specific SF-1 KO mice had considerably decreased expression in the region of the VMH of several genes, including brain-derived neurotrophic factor (BDNF), the type 2 receptor for corticotropin-releasing hormone (CRF-R_2), and the leptin receptor. These findings reveal important roles of SF-1 in the hypothalamic expression of key regulators of body weight and anxiety, providing a plausible molecular explanation for the phenotype caused by CNS-specific KO of SF-1.