THE ADIPOCYTE SPECIFIC TRANSCRIPTION FACTOR C EBP-ALPHA MODULATES HUMAN OB GENE-EXPRESSION/

The ob gene product, leptin, apparently exclusively expressed in adipo se tissue, is a signaling factor regulating body weight homeostasis an d energy balance. ob gene expression is increased in obese rodents and regulated by feeding, insulin, and glucocorticoids, which supports th e concept that ob gene expression is under hormonal control, which is expected for a key factor controlling body weight homeostasis and ener gy balance. In humans, ob mRNA expression is increased in gross obesit y; however, the effects of the above factors on human ob expression ar e unknown. We describe the structure of the human ob gene and initial functional analysis of its promoter. The human ob gene's three exons c over approximate to 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 th e initiator ATG codon. Three kilobases of DNA upstream of the transcri ption 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/EBP alpha. Mutation of the single C/EBP alpha site in this region abolished inducibility of the promoter by C/EBP alpha in cotransfection assays. The gene structu re will facilitate our analysis of ob mutations in human obesity, wher eas knowledge of sequence elements and factors regulating ob gene expr ession should be of major importance in the prevention and treatment o f obesity.