NUTRITIONAL AND INSULIN REGULATION OF FATTY-ACID SYNTHETASE AND LEPTIN GENE-EXPRESSION THROUGH ADD1 SREBP1/

The ability to regulate specific genes of energy metabolism in respons e to fasting and feeding is an important adaptation allowing survival of intermittent food supplies. However, little is known about transcri ption factors involved in such responses in higher organisms. We show here that gene expression in adipose tissue for adipocyte determinatio n differentiation dependent factor (ADD) 1/sterol regulatory element b inding protein (SREBP) 1, a basic-helix-loop-helix protein that has a dual DNA-binding specificity, is reduced dramatically upon fasting and elevated upon refeeding; this parallels closely the regulation of two adipose cell genes that are crucial in energy homeostasis, fatty acid synthetase (FAS) and leptin. This elevation of ADD1/SREBP1, leptin, a nd FAS that is induced by feeding in vivo is mimicked by exposure of c ultured adipocytes to insulin, the classic hormone of the fed state, W e also show that the promoters for both leptin and FAS are transactiva ted by ADD1/SREBP1, A mutation in the basic domain of ADD1/SREBP1 that allows E-box binding but destroys sterol regulatory element-1 binding prevents leptin gene transactivation but has no effect on the increas e in FAS promoter function. Molecular dissection of the FAS promoter s hows that most if not all of this action of ADD1/SREBP1 is through an E-box motif at -64 to -59, contained with a sequence identified previo usly as the major insulin response element of this gene, These results indicate that ADD1/SREBP1 is a key transcription factor linking chang es in nutritional status and insulin levels to the expression of certa in genes that regulate systemic energy metabolism.