title: Effects of ATF4 on PGC1α expression in brown adipose tissue and metabolic responses to cold stress.
abstract: OBJECTIVE
  We have shown previously that the expression of peroxisome proliferator activated receptor gamma coactivator (PGC1α) increases significantly in the white and brown adipose tissue of activating transcription factor 4 (ATF4) global knockout mice, which suggests that ATF4 is involved in the regulation of PGC1α expression. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms.
  
  
  METHODS
  The effects of ATF4 on PGC1α expression and on PGC1α promoter activity were analyzed in vivo and in vitro using mice, HIB-1B, and 293T cell line. The physiological functions of ATF4 in the regulation of PGC1α expression were confirmed by analysis of body temperature of Atf4(-/-) and Atf4(+/+) mice in response to cold stress as well as expression of Complex I, II, III, V in BAT.
  
  
  RESULTS
  In this study, we showed ATF4 to be a negative regulator of PGC1α expression through competitive binding with cAMP response element binding protein (CREB) at a cAMP response element (CRE) site in the PGC1α promoter. ATF4 was also found to influence the expression of mitochondria-related proteins, including Complex I, II, III, and IV through regulation of PGC1α. Finally, we showed that Atf4(-/-) mice have higher core body temperatures in reduced-temperature environments than control mice.
  
  
  CONCLUSIONS
  This study describes the mechanisms underlying ATF4 regulating PGC1α expression. We demonstrate a novel function of ATF4 in the regulation of thermogenesis. Taken together, these observations provide new insight into the physiological functions of ATF4, especially the regulation of thermogenesis and the response to cold stress.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, the Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Wang
authors.forename: Tingting
authors.initials: T
authors.lastname: Xia
authors.forename: Ying
authors.initials: Y
authors.lastname: Du
authors.forename: Qingshu
authors.initials: Q
authors.lastname: Meng
authors.forename: Houkai
authors.initials: H
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Shanghai
authors.initials: S
authors.lastname: Chen
authors.forename: Feifan
authors.initials: F
authors.lastname: Guo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis* / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001831:Body Temperature / Q000502:physiology; D002460:Cell Line; D058639:Cold-Shock Response / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022722:Thermogenesis / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: C081452:Atf4 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D012313:RNA