Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2004) 8 OC11

SFE2004 Oral Communications Neuroendocrinology and Reproduction (8 abstracts)

Brain-derived neurotrophic factor (BDNF) is a novel steroidogenic factor-1 (SF-1) target gene in the ventromedial hypothalamus (VMH): implications for obesity onset

RC Fowkes 1,2 , PV Tran 2 , SF Akana 2 , CR Carey 2 , MF Dallman 2 & HA Ingraham 2


1Veterinary Basic Sciences, Royal Veterinary College, London, UK; 2Physiology, University of California San Francisco, San Francisco, USA.

BDNF, a neurotrophin involved in brain development and plasticity, is implicated in the melanocortin regulation of obesity onset. Mice deficient in the orphan nuclear receptor SF-1 have a poorly developed VMH and consequent absence of BDNF in this region. Our studies reveal a role for SF-1 in BDNF expression, and its' implications for hypothalamic obesity. Real-time RT-PCR indicated expression of BDNF exons I, III and IV were dramatically reduced in the VMH of SF-1 heterozygous(HET) mice compared to wild-type(WT). Promoter analysis of these exons revealed at least 6 consensus SF-1 binding sites (AGGTCA), 4 of which bound SF-1 with similar affinity as determined by gel-shift assays. Transient co-transfection of a BDNF-IV-luciferase construct in placental JEG-3 cells with WT-SF-1 resulted in approximately 7.0-fold increase in promoter activity. Feeding experiments showed that SF-1-HET mice maintained on a high-fat diet (45kcal% fat) exhibited markedly greater weight gain than WT littermates. The physiological basis for the increased body weight was determined by measuring morning(AM) oxygen consumption as an indirect measure of metabolic rate in 10-week old WT and SF-1-HET mice maintained on control (10kcal% fat) or high-fat (45kcal% fat) diet for 5 weeks. On normal diet, HET oxygen(AM) consumption was higher than WT; on high-fat, WT increased oxygen(AM) consumption, while HET oxygen(AM) consumption was significantly lower than WT. These data imply SF-1-HETs on high-fat diet altered their energy output to maintain body weight. Moreover, SF-1 HET ate 25% more kcals than WT when offered a high-fat diet. This hyperphagia resembles the dynamic phase of rodents with VMH lesions. Therefore, BDNF is a novel SF-1 target gene that contributes to obesity onset in adult mice due to alterations in metabolic function. (supported by UCSF Sandler Award (HAI), NICHD NRSA (PVT), DK64180(SFA; RCF/PVT/SFA equal contribution))

Volume 8

195th Meeting of the Society for Endocrinology joint with Diabetes UK and the Growth Factor Group

Society for Endocrinology 

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