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

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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.