title: Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice.
abstract: OBJECTIVE
  The pancreas and hypothalamus are critical for maintaining nutrient and energy homeostasis, and combined disorders in these organs account for the onset of the metabolic syndrome. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. The physiological role of ATF3 in the pancreas has been controversial, and its role in the hypothalamus remains unknown. To elucidate the roles of ATF3 in these organs, we generated pancreas- and hypothalamus-specific Atf3 knockout (PHT-Atf3-KO) mice in this study.
  
  
  METHODS
  We crossed mice bearing floxed Atf3 alleles with Pdx1-cre mice, in which cre is specifically expressed in the pancreas and hypothalamus, and analysed metabolic variables, pancreatic morphology, food intake, energy expenditure and sympathetic activity in adipose tissue. We also used a hypothalamic cell line to investigate the molecular mechanism by which ATF3 regulates transcription of the gene encoding agouti-related protein (Agrp).
  
  
  RESULTS
  Although PHT-Atf3-KO mice displayed better glucose tolerance, neither plasma glucagon nor insulin level was altered in these mice. However, these mice exhibited higher insulin sensitivity, which was accompanied by a leaner phenotype due to decreased food intake and increased energy expenditure. We also observed decreased hypothalamic Agrp expression in PHT-Atf3-KO mice. Importantly, an increase in ATF3 levels is induced by fasting or low glucose in the hypothalamus. We also showed that ATF3 interacts with forkhead box-containing protein, O subfamily 1 (FoxO1) on the Agrp promoter and activates Agrp transcription.
  
  
  CONCLUSIONS
  Our results suggest that ATF3 plays an important role in the control of glucose and energy metabolism by regulating Agrp.
authors: Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma 371-8512, Japan.
authors: Y-S
authors: YS
authors: Lee
authors: T
authors: T
authors: Sasaki
authors: M
authors: M
authors: Kobayashi
authors: O
authors: O
authors: Kikuchi
authors: H-J
authors: HJ
authors: Kim
authors: H
authors: H
authors: Yokota-Hashimoto
authors: M
authors: M
authors: Shimpuku
authors: V-Y
authors: VY
authors: Susanti
authors: Y
authors: Y
authors: Ido-Kitamura
authors: K
authors: K
authors: Kimura
authors: H
authors: H
authors: Inoue
authors: M
authors: M
authors: Tanaka-Okamoto
authors: H
authors: H
authors: Ishizaki
authors: J
authors: J
authors: Miyoshi
authors: S
authors: S
authors: Ohya
authors: Y
authors: Y
authors: Tanaka
authors: S
authors: S
authors: Kitajima
authors: T
authors: T
authors: Kitamura
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D054369:Agouti-Related Protein / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D002460:Cell Line; D004734:Energy Metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D024821:Metabolic Syndrome / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011401:Promoter Regions, Genetic; D013997:Time Factors
chemical_list: D051700:Activating Transcription Factor 3; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; C103002:Atf3 protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; C045073:Cre recombinase; D019426:Integrases; D005947:Glucose