title: Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1.
abstract: The ability to regulate specific genes of energy metabolism in response to fasting and feeding is an important adaptation allowing survival of intermittent food supplies. However, little is known about transcription factors involved in such responses in higher organisms. We show here that gene expression in adipose tissue for adipocyte determination differentiation dependent factor (ADD) 1/sterol regulatory element binding 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, and FAS that is induced by feeding in vivo is mimicked by exposure of cultured adipocytes to insulin, the classic hormone of the fed state. We also show that the promoters for both leptin and FAS are transactivated 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 increase in FAS promoter function. Molecular dissection of the FAS promoter shows 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 previously as the major insulin response element of this gene. These results indicate that ADD1/SREBP1 is a key transcription factor linking changes in nutritional status and insulin levels to the expression of certain genes that regulate systemic energy metabolism.
authors.affiliation: Dana-Farber Cancer Institute, and Department of Cell Biology, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Kim
authors.forename: P
authors.initials: P
authors.lastname: Sarraf
authors.forename: M
authors.initials: M
authors.lastname: Wright
authors.forename: K M
authors.initials: KM
authors.lastname: Yao
authors.forename: E
authors.initials: E
authors.lastname: Mueller
authors.forename: G
authors.initials: G
authors.lastname: Solanes
authors.forename: B B
authors.initials: BB
authors.lastname: Lowell
authors.forename: B M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D016475:3T3 Cells; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004435:Eating; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018257:Helix-Loop-Helix Motifs; D007328:Insulin / Q000494:pharmacology; D020738:Leptin; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D015533:Transcriptional Activation
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D020738:Leptin; D009687:Nuclear Proteins; D011506:Proteins; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D064429:Fatty Acid Synthases