Leptin receptor 5 ' untranslated regions in the rat: relative abundance, genomic organization and relation to putative response elements

Hypothalamic sensitivity to leptin has been suggested to be important for r egulation of body fat mass. Mice heterozygous for a mutation in the leptin receptor (leptin-R) have an increased body fat mass suggesting that the abu ndance of leptin-R may be an important determinator of leptin sensitivity. Leptin-R cDNAs from several species contain alternative S'untranslated regi ons (5'UTRs), suggesting that several distinct regulatory regions may exist . To investigate possible mechanisms by which leptin-R expression may be re gulated, we searched for possible alternative 5'UTRs of the leptin-R in the rat and determined their location in relation to putative response element s. Four leptin-R 5'UTRs (exons IA-ID), which diverged 23 bp upstream of the start codon, were identified by 5'Rapid Amplification of cDNA Ends (5'RACE ) and sequencing. Exons 1B and 1C were present in 31 and 61%, respectively, of all leptin-R transcripts in the hypothalamus as determined by a ribonuc lease protection assay. Analysis of the 5' flanking genomic sequences revea led an imperfect estrogen response element (ERE), two Spl-sites, three CCAA T-boxes and one octamer. Exons 1A and 1D corresponded to a putative second gene, encoding the OB-Receptor Gene Related Protein (OB-RGRP), which is tra nscribed from a promoter shared with the leptin-R. DNA sequencing revealed that the rat OB-RGRP had 98 and 97% homology with the mouse and human seque nce, respectively. We report here that transcription of the rat leptin-R ge ne may generate transcripts with four alternative 5'UTRs. The presence of a putative ERE, close to the most frequently used transcriptional start site s of the leptin-R gene in the hypothalamus, provides a possible mechanism b y which estrogen may exert its effects on food intake. (C) 2000 Elsevier Sc ience Ireland Ltd. All rights reserved.