Transcription-start sites for the mouse and human beta 3-adrenergic-receptor mRNA have been localized in a region comprised between 150 and 200 nucleotides 5' from the ATG translation-start codon. Motifs potentially implicated in heterologous regulation of beta 3-adrenergic-receptor expression by glucocorticoids and by beta-adrenergic agonists have been identified upstream from these cap sites. In mouse, a second mRNA initiation region is postulated to exist further upstream. Comparison of the nucleotide sequences of the 3' end of the human and mouse beta 3-adrenergic-receptor genes to those of the corresponding cDNA revealed that in contrast to beta 1 and beta 2 adrenergic receptors, the beta 3-adrenergic-receptor genes comprise several exons. A large exon (1.4 kb) encodes the first 402 and 388 amino-acid residues of the human and mouse beta 3 adrenergic receptor, respectively. In man, a second exon (700 bp) contains the sequence coding for the six carboxy-terminal residues of the receptor and the entire mRNA 3' untranslated region. In mouse, a second exon (68 bp) codes for the 12 carboxy-terminal residues of the receptor and a third exon contains the beta 3-adrenergic-receptor mRNA 3' untranslated region. The use of alternate acceptor splice sites generates two forms of exon 3 (600 bp and 700 bp), yielding two beta 3-adrenergic-receptor transcripts which are differentially expressed in white and brown adipose tissues. Human beta 3-adrenergic-receptor transcripts with different 3' untranslated regions are produced by continuation of transcription beyond termination signals. Together, our results suggest that utilization of alternate promoters and/or 3' untranslated regions may allow tissue-specific regulation of beta 3-adrenergic-receptors expression.