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 controls lipogenesis and is induced during overnutrition 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, TFE3 is a novel bHLH transcription factor that strongly activates various insulin signaling molecules, protecting against the development of insulin resistance and the metabolic syndrome. 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 of glycogen synthesis to lipogenesis. In addition, these two transcription factors may ultimately contribute to pathophysiological effects of overnutrition leading to the 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.