Atf4 Regulates Obesity, Glucose Homeostasis, and Energy Expenditure Jin Seo 1 , Edgardo S. Fortuno III 1 , Jae Myoung Suh 1 , Drew Stenesen 1 , Wei Tang 1 , Elizabeth J. Parks 2 , Christopher M. Adams 3 , Tim Townes 4 and Jonathan M. Graff 1 , 2 , 5 1 Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas; 2 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; 3 Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa; 4 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama; 5 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas. Corresponding author: Jonathan M. Graff, jon.graff{at}utsouthwestern.edu . Abstract OBJECTIVE We evaluate a potential role of activating transcription factor 4 (Atf4) in invertebrate and mammalian metabolism. RESEARCH DESIGN AND 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. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received March 9, 2009. Accepted July 28, 2009. © 2009 American Diabetes Association