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

根据世界卫生组织的数据，肥胖症已达到流行病的程度，其中3亿人患有临床肥胖症。肥胖和超重是导致与饮食有关的严重慢性疾病的主要风险，包括II型糖尿病、心血管疾病和某些形式的癌症。肥胖是一个非常复杂的问题，似乎不仅仅是我们生活方式的结果。因此，了解这种代谢性疾病发展的分子机制对于寻找新的治疗途径具有重要意义。我们对肥胖发病机制的了解越来越多，揭示了这种疾病与脂质合成（脂肪生成）之间的密切联系。脂肪酸合成酶（FAS）是脂肪合成的关键酶。在目前的研究计划中，我们建议表征响应激素和营养物质调节FAS基因表达的分子机制。FAS被三碘甲状腺原氨酸（T3）和胰岛素上调，被胰高血糖素和中链脂肪酸（MCFA）下调。 我们以前已经证明，胰岛素和三碘甲状腺原氨酸（T3），两种饮食诱导的激素，上调FAS基因的表达和FAS酶活性在鸡胚肝细胞。然而，这些激素（胰岛素和T3）作用的确切机制仍有待表征。通过分析FAS基因的调控区（启动子），我们提出了确定调控FAS基因表达的分子机制，并证明了中链脂肪酸（己酸：C6）能够特异性下调胰岛素和T3诱导的FAS基因表达。这可能对开发营养添加剂以减少饮食引起的肥胖的目标具有极大的兴趣。因此，我们将描述MCFA作用的机制，并确定负责抑制FAS转录的代谢产物。

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.