Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage.
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.
Tran
Phu V
PV
Department of Physiology, University of California, San Francisco, San Francisco, California 94143, USA.
Akana
Susan F
SF
Malkovska
Irena
I
Dallman
Mary F
MF
Parada
Luis F
LF
Ingraham
Holly A
HA
D000818:Animals; D001835:Body Weight / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003080:Cold Temperature / Q000009:adverse effects; D005508:Food Deprivation / Q000502:physiology; D015870:Gene Expression / Q000235:genetics*; D018398:Homeodomain Proteins / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D020738:Leptin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D010101:Oxygen Consumption / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D054339:Steroidogenic Factor 1; D013312:Stress, Physiological / Q000209:etiology / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*; D014697:Ventromedial Hypothalamic Nucleus / Q000166:cytology / Q000502:physiology*; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D018398:Homeodomain Proteins; D020738:Leptin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C105974:acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide; C515058:steroidogenic factor 1, mouse; D000521:alpha-MSH