Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage

Phu V. Tran, Susan F. Akana, Irena Malkovska, Mary F. Dallman, Luis F. Parada, Holly A. Ingraham

Research output: Contribution to journalArticle

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)637-648
Number of pages12
JournalJournal of Comparative Neurology
Volume498
Issue number5
DOIs
StatePublished - Oct 10 2006

Keywords

  • Brain-derived neurotrophic factor (BDNF)
  • Exon BDNF transcripts
  • SF-1
  • Sympathetic tone
  • Ventromedlal hypothalamus (VMH, VMN)

ASJC Scopus subject areas

  • Neuroscience(all)

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    Tran, P. V., Akana, S. F., Malkovska, I., Dallman, M. F., Parada, L. F., & Ingraham, H. A. (2006). Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage. Journal of Comparative Neurology, 498(5), 637-648. https://doi.org/10.1002/cne.21070