title: Atf4 regulates obesity, glucose homeostasis, and energy expenditure.
abstract: OBJECTIVE
  We evaluate a potential role of activating transcription factor 4 (Atf4) in invertebrate and mammalian metabolism.
  
  
  METHODS
  With two parallel approaches-a fat body-specific green fluorescent protein enhancer trap screen in D. melanogaster and expression profiling of developing murine fat tissues-we identified Atf4 as expressed in invertebrate and vertebrate metabolic tissues. We assessed the functional relevance of the evolutionarily conserved expression by analyzing Atf4 mutant flies and Atf4 mutant mice for possible metabolic phenotypes.
  
  
  RESULTS
  Flies with insertions at the Atf4 locus have reduced fat content, increased starvation sensitivity, and lower levels of circulating carbohydrate. Atf4 null mice are also lean, and they resist age-related and diet-induced obesity. Atf4 null mice have increased energy expenditure potentially accounting for the lean phenotype. Atf4 null mice are hypoglycemic, even before substantial changes in fat content, indicating that Atf4 regulates mammalian carbohydrate metabolism. In addition, the Atf4 mutation blunts diet-induced diabetes as well as hyperlipidemia and hepatosteatosis. Several aspects of the Atf4 mutant phenotype resemble mice with mutations in components of the target of rapamycin (TOR) pathway. Consistent with the phenotypic similarities, Atf4 null mice have reduced expression of genes that regulate intracellular amino acid concentrations and lower intracellular concentration of amino acids, a key TOR input. Further, Atf4 mutants have reduced S6K activity in liver and adipose tissues.
  
  
  CONCLUSIONS
  Atf4 regulates age-related and diet-induced obesity as well as glucose homeostasis in mammals and has conserved metabolic functions in flies.
authors.affiliation: Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Seo
authors.forename: Edgardo S
authors.initials: ES
authors.lastname: Fortuno
authors.forename: Jae Myoung
authors.initials: JM
authors.lastname: Suh
authors.forename: Drew
authors.initials: D
authors.lastname: Stenesen
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Parks
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Adams
authors.forename: Tim
authors.initials: T
authors.lastname: Townes
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Graff
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000502:physiology; D000596:Amino Acids / Q000097:blood; D000818:Animals; D017124:Conserved Sequence; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000517:prevention & control; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D004734:Energy Metabolism; D005227:Fatty Acids / Q000032:analysis; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006706:Homeostasis; D007003:Hypoglycemia / Q000235:genetics; D007814:Larva / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains / Q000235:genetics; D008822:Mice, Transgenic; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D010641:Phenotype
chemical_list: D000596:Amino Acids; C081452:Atf4 protein, mouse; D005227:Fatty Acids; D051701:Activating Transcription Factor 4; D049452:Green Fluorescent Proteins; D000242:Cyclic AMP; D005947:Glucose
references.citation: Science. 2004 Oct 15;306(5695):457-61
references.pmid: 15486293
references.citation: Cell. 2006 Aug 25;126(4):727-39
references.pmid: 16923392
references.citation: Nature. 2006 Dec 14;444(7121):854-9
references.pmid: 17167473
references.citation: Cell Metab. 2008 Jun;7(6):520-32
references.pmid: 18522833
references.citation: Mol Cell. 2003 Mar;11(3):619-33
references.pmid: 12667446
references.citation: J Lipid Res. 1978 Mar;19(3):316-24
references.pmid: 206638
references.citation: Nat Med. 2001 Oct;7(10):1128-32
references.pmid: 11590436
references.citation: Curr Opin Cell Biol. 2005 Apr;17(2):167-73
references.pmid: 15780593
references.citation: Curr Med Chem. 2004 Apr;11(7):901-8
references.pmid: 15078172
references.citation: Hypertension. 1997 Nov;30(5):1144-9
references.pmid: 9369268
references.citation: Mech Dev. 2000 May;93(1-2):151-60
references.pmid: 10781948
references.citation: Cell. 2008 Sep 19;134(6):933-44
references.pmid: 18805087
references.citation: Genetics. 2000 Aug;155(4):1711-23
references.pmid: 10924469
references.citation: Cell. 2004 Apr 30;117(3):387-98
references.pmid: 15109498
references.citation: Nat Clin Pract Endocrinol Metab. 2007 Jun;3(6):458-69
references.pmid: 17515890
references.citation: Curr Opin Cell Biol. 2005 Dec;17(6):596-603
references.pmid: 16226444
references.citation: Antioxid Redox Signal. 2007 Dec;9(12):2357-71
references.pmid: 17760508
references.citation: J Clin Invest. 2008 Oct;118(10):3378-89
references.pmid: 18776938
references.citation: Science. 2008 Jun 13;320(5882):1496-501
references.pmid: 18497260
references.citation: Dev Cell. 2008 Dec;15(6):829-40
references.pmid: 19081072
references.citation: Cell Metab. 2006 Dec;4(6):441-51
references.pmid: 17141628
references.citation: Physiol Rev. 2006 Oct;86(4):1133-49
references.pmid: 17015486
references.citation: Annu Rev Nutr. 2007;27:293-310
references.pmid: 17666010
references.citation: Genes Dev. 2005 Aug 15;19(16):1844-8
references.pmid: 16103212
references.citation: Cell Metab. 2007 Sep;6(3):195-207
references.pmid: 17767906
references.citation: J Gerontol. 1989 Mar;44(2):M66-73
references.pmid: 2921472
references.citation: J Biol Chem. 2007 Jun 8;282(23):16744-53
references.pmid: 17430894
references.citation: Genes Cells. 1998 Dec;3(12):801-10
references.pmid: 10096021
references.citation: Cell Metab. 2006 Jun;3(6):393-402
references.pmid: 16753575
references.citation: Mol Cell. 2001 Jun;7(6):1165-76
references.pmid: 11430820
references.citation: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17175-80
references.pmid: 18957537
references.citation: Nature. 2006 Dec 14;444(7121):847-53
references.pmid: 17167472
references.citation: Diabetes. 2005 Sep;54(9):2674-84
references.pmid: 16123357
references.citation: Proc Natl Acad Sci U S A. 1990 Dec;87(24):9590-4
references.pmid: 2263614
references.citation: Nat Rev Mol Cell Biol. 2002 Jun;3(6):411-21
references.pmid: 12042763
references.citation: Endocr Rev. 2008 May;29(3):317-33
references.pmid: 18436705
references.citation: Blood. 2002 Feb 1;99(3):736-45
references.pmid: 11806972
references.citation: Nature. 2004 Sep 9;431(7005):200-5
references.pmid: 15306821
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: Cell Metab. 2006 Aug;4(2):133-42
references.pmid: 16890541
references.citation: Nature. 2000 Apr 6;404(6778):635-43
references.pmid: 10766250
references.citation: Mol Cell. 2001 Jun;7(6):1153-63
references.pmid: 11430819
references.citation: Development. 1994 Sep;120(9):2489-99
references.pmid: 7956826