title: Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1-Egr1-ATGL-mediated pathway.
abstract: One of the basic functions of insulin in the body is to inhibit lipolysis in adipocytes. Recently, we have found that insulin inhibits lipolysis and promotes triglyceride storage by decreasing transcription of adipose triglyceride lipase via the mTORC1-mediated pathway (P. Chakrabarti et al., Diabetes 59:775-781, 2010), although the mechanism of this effect remained unknown. Here, we used a genetic screen in Saccharomyces cerevisiae in order to identify a transcription factor that mediates the effect of Tor1 on the expression of the ATGL ortholog in yeast. This factor, Msn4p, has homologues in mammalian cells that form a family of early growth response transcription factors. One member of the family, Egr1, is induced by insulin and nutrients and directly inhibits activity of the ATGL promoter in vitro and expression of ATGL in cultured adipocytes. Feeding animals a high-fat diet increases the activity of mTORC1 and the expression of Egr1 while decreasing ATGL levels in epididymal fat. We suggest that the evolutionarily conserved mTORC1-Egr1-ATGL regulatory pathway represents an important component of the antilipolytic effect of insulin in the mammalian organism.
authors.affiliation: Boston University School of Medicine, Boston, Massachusetts, USA. pc1@csiriicb.in
authors.forename: Partha
authors.initials: P
authors.lastname: Chakrabarti
authors.forename: Ju Youn
authors.initials: JY
authors.lastname: Kim
authors.forename: Maneet
authors.initials: M
authors.lastname: Singh
authors.forename: Yu-Kyong
authors.initials: YK
authors.lastname: Shin
authors.forename: Jessica
authors.initials: J
authors.lastname: Kim
authors.forename: Joerg
authors.initials: J
authors.lastname: Kumbrink
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Lee
authors.forename: Kathrin H
authors.initials: KH
authors.lastname: Kirsch
authors.forename: Susan K
authors.initials: SK
authors.lastname: Fried
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Kandror
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008066:Lipolysis; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D007328:Insulin; D008049:Lipase; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D029701:Saccharomyces cerevisiae Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C486109:Egr1 protein, mouse; C081937:MSN4 protein, S cerevisiae; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases; C506904:Tgl4 protein, S cerevisiae