Role of medium chain fatty acids in the regulation of fatty acid synthase

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According to the World Health Organization, obesity has reached epidemic proportions with 300 millions of them clinically obese. Obesity and overweight pose a major risk for serious diet-related chronic diseases, including type II diabetes, cardiovascular diseases, and certain forms of cancer. Obesity is a very complex problem and does not appear to be only a consequence of our way of life. Therefore, understanding the molecular mechanisms underlying the development of this metabolic disease is important in the aim to find new therapy avenues.Our increasing understanding of the pathogenesis of obesity has revealed a strong link between this disorder and de novo lipid synthesis (lipogenesis). Among the enzymes involved in lipogenesis, Fatty Acid Synthase (FAS) has been showed to be a crucial biosynthetic enzyme. In the present research program, we propose to characterize the molecular mechanisms regulating the FAS gene expression in response to hormones and nutrients. FAS is up-regulated by triiodothyronine (T3) and insulin and down-regulated by glucagon and medium-chain fatty acids (MCFAs).  We have previously demonstrated that both insulin and triiodothyronine (T3), two diet-induced hormones, up regulate the FAS gene expression and the FAS enzymatic activity in chick embryo hepatocytes. The precise mechanism of these hormonal (insulin and T3) actions remains however to be characterize. We propose to identify the molecular mechanisms that regulate the expression of the FAS gene analysing the regulatory region of the gene (promoter).We have also demonstrated that a medium chain fatty acid (hexanoate:C6) is able to specifically down-regulate insulin and T3-induced FAS gene expression. This may be of great interest in the aim to develop nutrient additives to decrease diet-induced obesity. We will therefore characterize the mechanism of the MCFA action and identified the metabolite that is responsible for the inhibition of FAS transcription.