title: AMPK/α-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis.
abstract: Promoting brown adipose tissue (BAT) development is an attractive strategy for the treatment of obesity, as activated BAT dissipates energy through thermogenesis; however, the mechanisms controlling BAT formation are not fully understood. We hypothesized that as a master regulator of energy metabolism, AMP-activated protein kinase (AMPK) may play a direct role in the process and found that AMPKα1 (PRKAA1) ablation reduced Prdm16 expression and impaired BAT development. During early brown adipogenesis, the cellular levels of α-ketoglutarate (αKG), a key metabolite required for TET-mediated DNA demethylation, were profoundly increased and required for active DNA demethylation of the Prdm16 promoter. AMPKα1 ablation reduced isocitrate dehydrogenase 2 activity and cellular αKG levels. Remarkably, postnatal AMPK activation with AICAR or metformin rescued obesity-induced suppression of brown adipogenesis and thermogenesis. In summary, AMPK is essential for the epigenetic control of BAT development through αKG, thus linking a metabolite to progenitor cell differentiation and thermogenesis.
authors.affiliation: Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Xingwei
authors.initials: X
authors.lastname: Liang
authors.affiliation: School of Food Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Sun
authors.affiliation: Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA; Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
authors.forename: Lupei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Fu
authors.affiliation: Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Rogers
authors.affiliation: Institute of Biological Chemistry, Washington State University, Pullman, WA 99164, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Berim
authors.affiliation: School of Food Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Shuming
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Songbo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France; CNRS UMR 8104, 75014 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Institute of Biological Chemistry, Washington State University, Pullman, WA 99164, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Gang
authors.affiliation: Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Buel D
authors.initials: BD
authors.lastname: Rodgers
authors.affiliation: School of Food Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Mei-Jun
authors.initials: MJ
authors.lastname: Zhu
authors.affiliation: Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100194, China. Electronic address: min.du@wsu.edu.
authors.forename: Min
authors.initials: M
authors.lastname: Du
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics*; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D002460:Cell Line; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D007656:Ketoglutaric Acids / Q000378:metabolism*; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics; D011401:Promoter Regions, Genetic; D017154:Stromal Cells / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014886:Weaning
chemical_list: D004268:DNA-Binding Proteins; D007656:Ketoglutaric Acids; C521133:Prdm16 protein, mouse; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases
keywords: DNA demethylation; Prkaa1; brown adipogenesis