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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Body Weight / genetics
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Brain-Derived Neurotrophic Factor / genetics
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Brain-Derived Neurotrophic Factor / metabolism*
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Cold Temperature / adverse effects
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Food Deprivation / physiology
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Gene Expression / genetics*
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Homeodomain Proteins / physiology*
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Immunohistochemistry / methods
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Leptin / blood
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neurons / metabolism
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Oxygen Consumption / genetics
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Promoter Regions, Genetic / physiology
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / deficiency
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Receptors, Cytoplasmic and Nuclear / physiology*
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Steroidogenic Factor 1
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Stress, Physiological / etiology
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Stress, Physiological / genetics
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Transcription Factors / deficiency
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Transcription Factors / physiology*
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Ventromedial Hypothalamic Nucleus / cytology
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Ventromedial Hypothalamic Nucleus / physiology*
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alpha-MSH / analogs & derivatives
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alpha-MSH / pharmacology
Substances
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Brain-Derived Neurotrophic Factor
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Homeodomain Proteins
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Leptin
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Steroidogenic Factor 1
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Transcription Factors
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acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide
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steroidogenic factor 1, mouse
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alpha-MSH