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Department of Nutrition and Agricultural Experiment Station, University of Tennessee, Knoxville, TN 37996-1920;
* Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN;
Division of Plastic Surgery, Department of Surgery, University of Tennessee Medical Center, Knoxville, TN;
** Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, TN;
Department of Food Science and Nutrition, Michigan State University, E. Lansing, MI; and
Department of Animal Science, University of Tennessee, Knoxville, TN
2To whom correspondence should be addressed. E-mail: moustaid{at}utk.edu.
Despite its potential importance in obesity and related disorders, little is known about regulation of lipogenesis in human adipose tissue. To investigate this area at the molecular and mechanistic levels, we studied lipogenesis and the regulation of 1 of its core enzymes, fatty acid synthase (FAS), in human adipose tissue in response to hormonal and nutritional manipulation. As a paradigm for lipogenic genes, we cloned the upstream region of the human FAS gene, compared its sequence to that of FAS orthologs from other species, and identified important regulatory elements that lie upstream of the FAS coding region. Lipogenesis, as assessed by glucose incorporation into lipids, was increased by insulin and more so by the combination of insulin and dexamethasone (Dex, a potent glucocorticoid analogue). In parallel, FAS expression, activity, and gene transcription rate were also significantly increased by these treatments. We also showed that linoleic acid, a representative PUFA, attenuated the actions of insulin and Dex on fatty acid and lipid synthesis as well as FAS activity and expression. Using reporter assays, we determined that the regions responsible for hormonal regulation of the FAS gene lie in the proximal portion of the gene’s 5'-flanking region, within which we identified an insulin response element similar to the E-box sequence we identified previously in the rat FAS gene. In summary, we demonstrated that lipogenesis occurs in human adipose tissue and can be induced by insulin, further enhanced by glucocorticoids, and suppressed by PUFA in a hormone-dependent manner.
KEY WORDS: • linoleic acid • insulin • dexamethasone • sequence • gene transcription
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