Insulin-glucocorticoid interactions in the regulation of acetyl-CoA carboxylase-alpha transcript diversity in ovine adipose tissue

Transcription of the acetyl-CoA carboxylase (ACC)-alpha gene is initiated f rom two promoters, promoter I (PI) and promoter II (PII) such that transcri pts demonstrate heterogeneity in their 5' untranslated regions (UTR). Exons 1 and 2 (E1 and E2) are the primary exons in transcripts initiated from PI and PII respectively; E5 is the first coding exon present in all transcrip ts. In addition alternative exon splicing results in transcripts that eithe r include or exclude a 47 nucleotide sequence corresponding to E4, such tha t E[1/4/5] and E[1/5] type transcripts result from PI activity, whereas tra nscripts containing E[2/4/5] or E[2/5] in the 5'UTR result from PII. In sub cutaneous adipose tissue from non-pregnant non-lactating sheep approximatel y 60% of ACC-alpha transcripts are derived from PI, of which 85% are the E[ 1/5] type. Lactation resulted in an 88% reduction in total PI transcripts, of which the E[1/5] type was reduced 90% and the E[1/4/5] type 80%. By cont rast lactation reduced the total levels of PII transcripts by only 50%. Cul ture of explants from the subcutaneous depot of lactating sheep with insuli n plus dexamethasone for 72 h resulted in an 8-fold increase in both E[1/4/ 5] and E[1/5] types when compared with explants prior to culture. PII trans cripts, bq contrast, were increased 2-fold by culture in insulin plus dexam ethasone and this was entirely attributed to an increase in the expression of the E[2/4/5] type. Dexamethasone acts to potentiate the action of insuli n on PI and PII transcript abundance and this effect is greatest for PI tra nscripts. This study has demonstrated that repression of the ACC-a gene in adipose tissue during lactation is largely achieved through attenuation of PI transcript abundance and may be related, in part, to a change in the sen sitivity of the apparatus that regulates PI transcript steady-state levels to insulin.