title: Feedback looping between ChREBP and PPARα in the regulation of lipid metabolism in brown adipose tissues.
abstract: Carbohydrate response element binding protein (ChREBP) and peroxisome proliferator-activated receptor alpha (PPARα) play an important role in the regulation of lipid metabolism in the liver. Chrebp and Ppara mRNA levels are equally abundant in brown adipose tissue and liver. However, their functions in brown adipose tissues are unclear. In this study, we attempted to clarify the role of ChREBP and PPARα using brown adipose HB2 cell lines and tissues from wild type and Chrebp-/- C57BL/6J mice. In liver and brown adipose tissues, Chrebpb mRNA levels in the fasting state were much lower than those fed ad libitum, while Ppara mRNA levels in the fasting state were much higher than in the fed state. In differentiated brown adipose HB2 cell lines, glucose increased mRNA levels of ChREBP target genes such as Chrebpb, Fasn, and Glut4 in a dose dependent manner, while glucose decreased both Chrebpa and Ppara mRNA levels. Accordingly, adenoviral overexpression of ChREBP and a reporter assay demonstrated that ChREBP partially suppressed Ppara and Acox mRNA expression. Moreover, in brown adipose tissues from Chrebp-/- mice, Chrebpb and Fasn mRNA levels in the ad libitum fed state were much lower than those in the fasting state, while Ppara and Acox mRNA levels were not. Finally, using Wy14,643, a selective PPARα agonist, and overexpression of PPARα partially suppressed glucose induction of Chrebpb and Fasn mRNA in HB2 cells. In conclusion, the feedback loop between ChREBP and PPARα plays an important role in the regulation of lipogenesis in brown adipocytes.
authors.affiliation: Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Iizuka
authors.forename: Wudelehu
authors.initials: W
authors.lastname: Wu
authors.forename: Yukio
authors.initials: Y
authors.lastname: Horikawa
authors.forename: Masayuki
authors.initials: M
authors.lastname: Saito
authors.forename: Jun
authors.initials: J
authors.lastname: Takeda
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002454:Cell Differentiation; D002460:Cell Line; D005215:Fasting; D054890:Fatty Acid Synthase, Type I / Q000096:biosynthesis; D025461:Feedback, Physiological / Q000502:physiology; D005502:Food; D005947:Glucose / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000502:physiology*; D047493:PPAR alpha / Q000819:agonists / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D014157:Transcription Factors; C006253:pirinixic acid; D054890:Fatty Acid Synthase, Type I; D005947:Glucose