title: 4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL.
abstract: Early growth response transcription factor Egr1 controls multiple aspects of cell physiology and metabolism. In particular, Egr1 suppresses lipolysis and promotes fat accumulation in adipocytes by inhibiting the expression of adipose triglyceride lipase. According to current dogma, regulation of the Egr1 expression takes place primarily at the level of transcription. Correspondingly, treatment of cultured adipocytes with insulin stimulates expression of Egr1 mRNA and protein. Unexpectedly, the MEK inhibitor PD98059 completely blocks insulin-stimulated increase in the Egr1 mRNA but has only a moderate effect on the Egr1 protein. At the same time, mTORC1 inhibitors rapamycin and PP242 suppress expression of the Egr1 protein and have an opposite effect on the Egr1 mRNA. Mouse embryonic fibroblasts with genetic ablations of TSC2 or 4E-BP1/2 express less Egr1 mRNA but more Egr1 protein than wild type controls. (35)S-labeling has confirmed that translation of the Egr1 mRNA is much more effective in 4E-BP1/2-null cells than in control. A selective agonist of the CB1 receptors, ACEA, up-regulates Egr1 mRNA, but does not activate mTORC1 and does not increase Egr1 protein in adipocytes. These data suggest that although insulin activates both the Erk and the mTORC1 signaling pathways in adipocytes, regulation of the Egr1 expression takes place predominantly via the mTORC1/4E-BP-mediated axis. In confirmation of this model, we show that 4E-BP1/2-null MEFs express less ATGL and accumulate more fat than control cells, while knock down of Egr1 in 4E-BP1/2-null MEFs increases ATGL expression and decreases fat storage.
authors: From the Boston University School of Medicine, Boston, Massachusetts 02118.
authors: Maneet
authors: M
authors: Singh
authors: From the Boston University School of Medicine, Boston, Massachusetts 02118.
authors: Yu-Kyong
authors: YK
authors: Shin
authors: From the Boston University School of Medicine, Boston, Massachusetts 02118.
authors: Xiaoqing
authors: X
authors: Yang
authors: From the Boston University School of Medicine, Boston, Massachusetts 02118.
authors: Brad
authors: B
authors: Zehr
authors: From the Boston University School of Medicine, Boston, Massachusetts 02118.
authors: Partha
authors: P
authors: Chakrabarti
authors: From the Boston University School of Medicine, Boston, Massachusetts 02118 kkandror@bu.edu.
authors: Konstantin V
authors: KV
authors: Kandror
mesh_terms: D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008049:Lipase / Q000378:metabolism*; D050356:Lipid Metabolism; D008066:Lipolysis; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000217:Acyltransferases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D051766:Early Growth Response Protein 1; D039642:Eukaryotic Initiation Factors; D007328:Insulin; D008049:Lipase; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; C497325:EGR1 protein, human; C486109:Egr1 protein, mouse; C499527:Eif4ebp1 protein, mouse; C491255:Eif4ebp2 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases
keywords: adipose triglyceride lipase (ATGL); early growth response protein 1 (EGR1); insulin; lipolysis; mammalian target of rapamycin (mTOR)