Study on a novel energy metabolism transcription factor that regulates insulin signaling

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Genes involved in carbohydrate and lipid metabolism are nutritionally regulated at the transcriptional level in a coordinated fashion. SREBP-1c is a bHLH transcription factor that control lipogenesis and is induced during over-nutrition to facilitate the conversion of glucose to fatty acids and triglycerides for the storage of the excess energy. Uncontrolled activation of nuclear SREBP-1c in the liver can cause hepatosteatosis, hypertriglyceridemia, and hepatic insulin resistance due to direct suppression of insulin signaling pathways, precipitating development of metabolic syndrome. Conversely, in an attempt to seek for a novel factor that could have therapeutic effects on obesity- or insulin resistance-related disorders, we identified TFE3, a novel bHLH transcription factor that activates various insulin signaling molecules, protecting against the development of insulin resistance and the metabolic syndrome. In this project, we conducted experiments to investigate impacts of this nov … More el factor on glucose and lipid metabolism. Adenoviral over-expression of TFE3 strongly activated gene expression of IRS-2, Akt1, Hexokinase II in the liver, leading to amelioration of insulin resistance and reduction in plasma glucose levels in several diabetic models such as db/db, KK-Ay, and diet-induced obesity mice as well as STZ-teated diabetic mice. Regulation of IRS-2 is the primary site where TFE3 in synergy with Foxo1, and SREBP-1c converge. Taken together, TFE3/Foxo1 and SREBP-1c reciprocally regulate IRS-2 expression and insulin sensitivity in the liver. This scenario provides a mechanistic explanation for the physiological link between glucose and lipid metabolism such as physiological switching glycogen synthesis to lipogenesis. In addition, these two transcription factors may ultimately contribute to pathophysiological effects of over-nutrition leading to development of the metabolic syndrome and diabetes. In this review I will discuss roles of SREBP-1c and TFE3 in homeostasis of energy metabolism and in metabolic disturbances, focusing on hepatic insulin sensitivity. Less