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Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and Hypertension-Endocrine Branch, National Heart, Lung, and Blood Institute (H.C., M.J.Q.), National Institutes of Health, Bethesda, Maryland 20892-1770
Address all correspondence and requests for reprints to: Dr. Marc Reitman, Diabetes Branch, Building 10, Room 8N-250, 10 Center Drive, MSC 1770, Bethesda, Maryland 20892-1770. E-mail: mlr{at}helix.nih.gov
Leptin is a hormone produced in adipose cells that regulates energy
expenditure, food intake, and adiposity. To understand leptin’s
transcriptional regulation, we are studying its promoter. Four
conserved and functional regions were identified. Mutations in the
C/EBP and TATA motifs each caused an approximately 10-fold decrease in
promoter activity. The C/EBP motif bound recombinant C/EBP
and
mediated trans-activation by C/EBP, -ß, and -
.
Mutation of a consensus Sp1 site reduced promoter activity 2.5-fold and
abolished binding of Sp1. Mutation of a fourth factor-binding site,
denoted LP1, abolished protein binding and reduced promoter activity
2-fold. Factor binding to the LP1 motif was observed with adipocyte,
but not with nonadipocyte extracts. Adipocytes from
fa/fa Zucker rats transcribed the reporter plasmids more
efficiently than did control adipocytes. No effect on the transient
expression of leptin was noted upon treatment with a thiazolidinedione,
BRL49653, or upon cotransfection with peroxisome proliferator-activated
receptor-
/retinoid X receptor- or sterol response element-binding
protein-1. Mutations of the Sp1, LP1, and C/EBP sites in pairwise
combinations diminished promoter activity to the extent predicted
assuming these motifs contribute independently to leptin promoter
function. Our identification of motifs regulating leptin transcription
is an important step in the elucidation of the mechanisms underlying
hormonal and metabolic regulation of this gene.
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