Here's the leptin abstract that generated the LGND all time high last
spring. Reuter's has announced that LGND will sign a leptin deal
this month:
Proc. Natl. Acad. Sci. U.S.A. 93: 5507-5511 (1996)
The adipocyte specific transcription factor C/EBPalpha
modulates human ob gene expression.
Miller SG, De Vos P, Guerre-Millo M, Wong K, Hermann T, Staels B, Briggs MR,
Auwerx J
Ligand Pharmaceuticals, Inc., San Diego, CA 92121, USA.
The ob gene product, leptin, apparently exclusively expressed in adipose tissue, is a signaling factor
regulating body weight homeostasis and energy balance. ob gene expression is increased in obese
rodents and regulated by feeding, insulin, and glucocorticoids, which supports the concept that ob
gene expression is under hormonal control, which is expected for a key factor controlling body
weight homeostasis and energy balance. In humans, ob mRNA expression is increased in gross
obesity; however, the effects of the above factors on human ob expression are unknown. We
describe the structure of the human ob gene and initial functional analysis of its promoter. The human
ob gene's three exons cover approximately 15 kb of genomic DNA. The entire coding region is
contained in exons 2 and 3, which are separated by a 2-kb intron. The first small 30-bp untranslated
exon is located >10.5 kb upstream of the initiator ATG codon. Three kilobases of DNA upstream of
the transcription start site has been cloned and characterized. Only 217 bp of 5' sequence are
required for basal adipose tissue-specific expression of the ob gene as well as enhanced expression
by C/EBPalpha. Mutation of the single C/EBPalpha site in this region abolished inducibility of the
promoter by C/EBPalpha in cotransfection assays. The gene structure will facilitate our analysis of ob
mutations in human obesity, whereas knowledge of sequence elements and factors regulating ob gene
expression should be of major importance in the prevention and treatment of obesity.
Henry |
