Chronic docosahexaenoic acid intake enhances expression of the gene for uncoupling protein 3 and affects pleiotropic mRNA levels in skeletal muscle of aged C57BU6NJcl mice

Docosahexaenoic acid [DHA, 22:6(n-3)] prevents cardiovascular disease by decreasing obesity. It also prevents cancer and other geriatric diseases. We studied the chronic pleiotropic effects of DHA on transcription including that of mRNAs for uncoupling proteins (UCP). Male and female mice (9 mo old) were fed high (n-6) or high (n-3) fatty acid diets for 4 mo. Compared with controls fed high (n-6) fatty acid diets [high (n-6) group], the livers of male and female mice fed DHA [high (n-3) group] contained six- (P < 0.001) and fivefold (P < 0.001) more DHA, respectively. The high (n-3) group had less white adipose tissue [35.3% in males (P < 0.001) and 27.3% in females (P < 0.001)]. The high (n-3) group expressed more uncoupling protein 3 (UCP3) in the gastrocnemius, 108% higher (P < 0.001) and 104% higher (P < 0.001) in males and females, respectively, than those in the high (n-6) group. However, the prevention of many diseases by DHA is not explained by UCP3. Thus, the gene expression profiles of both high (n-3) and high (n-6) groups were analyzed in skeletal muscle using cDNA expression array. Of 588 genes surveyed in the array, the high (n-3) group showed 12 genes (2%) including those for glucose regulators (e.g., CD38) and tumor suppressors (e.g., CTCF) that were expressed 100-340% more than those of the high (n-6) group. Furthermore, 28 genes (4.8%), including growth factors (e.g., ErbB-2 receptor) and immune regulators (e.g., interleukin-1 beta precursor) were expressed 50-90% less in the high (n-3) group than in the high (n-6) group. These results explain in part the important pleiotropic effects of DHA, which are independent of obesity control by UCP3 suppression.