The Human Fatty Acid Synthase Gene and De Novo Lipogenesis Are Coordinately Regulated in Human Adipose Tissue

Abstract

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.

Fatty acid synthase gene expression in human adipose tissue: association with obesity and type 2 diabetes

“…Data are log transformed to achieve normal distribution [8,9]. In a recent study it was demonstrated that insulin, both alone and in combination with dexamethasone, increased human FASN gene expression and concomitantly elevated FASN activity [24]. Although the contribution of human adipose tissue to whole-body lipogenesis is considered to be low and less than that of liver [6,7], adipose tissue remains an important site of endogenous fatty acid synthesis [25].…”

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

“…Yet, in the presence of elevated insulin, cortisol synergistically stimulates lipogenesis ( Fig. 1) (Ottosson et al 1994, Wang et al 2004. The metabolic response of adipose tissue to glucocorticoids also depends on the duration of exposure.…”

Metabolic action of peroxisome proliferator-activated receptor γ agonism in rats with exogenous hypercorticosteronemia

“…Because GC cumulate stimulatory actions on both lipogenic and lipolytic processes, 23 the net effect of GC on adipose tissue lipid metabolism is highly dependent upon many factors, including levels of GC themselves, interactions with other hormonal systems such as insulin, 34 and regional specificity. 29,35,36 Knowledge of the detailed mechanisms by which GC impact adipose tissue lipid metabolism remains fragmentary; however, a permissive action on the insulin-mediated stimulation of LPL, 37,38 an inhibitory effect on the anti-lipolytic action of insulin, 39 direct transcriptional activation of the fatty acid-synthesizing gene FAS, 40 and inhibition of the expression of the fatty acid re-esterification gene PEPCK 41 have been established. In the case of PPARg, effects on adipose tissue lipid metabolism are manifold and include stimulation of lipid uptake, esterification, recycling, lipolysis, and oxidation, 11,[42][43][44] with an overall preponderance of lipid retention over fatty acid release pathways explaining fat accretion.…”