title: The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling.
abstract: FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erbα, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erbα for Rev-erbα-binding sites identified βKlotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erbα in white adipose tissue but not liver. Rev-erbα ablation led to the robust elevated expression of βKlotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Rev-erbα. A major Rev-erbα-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) γ, which regulates its activity in the opposite direction. These findings establish Rev-erbα as a specific modulator of FGF21 signaling in adipose tissue.
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jager
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Wang
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Hee-Woong
authors.initials: HW
authors.lastname: Lim
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Lindsey C
authors.initials: LC
authors.lastname: Peed
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: David J
authors.initials: DJ
authors.lastname: Steger
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.affiliation: the Department of Chemistry, Indiana University Bloomington, Bloomington, Indiana 47405, and.
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.affiliation: the Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine and Genetics, and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, lazar@mail.med.upenn.edu.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C418622:Klb protein, mouse; D008565:Membrane Proteins; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D047495:PPAR gamma; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins
keywords: DNA binding protein; Rev-ErbAα (NR1D1); adipose tissue metabolism; clock gene; metabolic regulation; microarray; mouse; nuclear receptor; transcription enhancer