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  • Title: Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage.
    Author: Tran PV, Akana SF, Malkovska I, Dallman MF, Parada LF, Ingraham HA.
    Journal: J Comp Neurol; 2006 Oct 10; 498(5):637-48. PubMed ID: 16917842.
    Abstract:
    In the central nervous system, steroidogenic factor 1 (SF-1) is required for terminal differentiation of neurons within the ventromedial hypothalamus (VMH). Given the importance of this brain region in regulating physiological homeostasis including energy balance, we asked how sf-1 gene dosage affects VMH function. Despite an apparent normal VMH cytoarchitecture, sf-1 heterozygous (+/-) mice exhibited diet-induced obesity when they were group housed with hyperphagia and impaired sympathetic activity. On the basis of previous findings suggesting brain-derived neurotrophic factor (bdnf) as an SF-1 target gene, we assessed the colocalization of SF-1 and BDNF expressing neurons, as well as expression of the four exon-specific bdnf promoter transcripts in the VMH. Indeed, a subset of neurons located primarily in the ventrolateral VMH coexpress SF-1 and BDNF, and in contrast to other brain regions, bdnf I, II, and IV but not III are found. Consistent with these findings, cellular assays showed that SF-1 is able to activate exon I and IV promoters. More important, levels of bdnf I and IV in the VMH were reduced in heterozygous mice similar to levels observed in fasted wild-type mice. Collectively, we propose that a reduction in the sf-1 gene dosage directly affects BDNF levels in the VMH and disrupts normal hypothalamic function.
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