title: The Glucose Sensor ChREBP Links De Novo Lipogenesis to PPARγ Activity and Adipocyte Differentiation.
abstract: Reduced de novo lipogenesis in adipose tissue, often observed in obese individuals, is thought to contribute to insulin resistance. Besides trapping excess glucose and providing for triglycerides and energy storage, endogenously synthesized lipids can function as potent signaling molecules. Indeed, several specific lipids and their molecular targets that mediate insulin sensitivity have been recently identified. Here, we report that carbohydrate-response element-binding protein (ChREBP), a transcriptional inducer of glucose use and de novo lipogenesis, controls the activity of the adipogenic master regulator peroxisome proliferator-activated receptor (PPAR)γ. Expression of constitutive-active ChREBP in precursor cells activated endogenous PPARγ and promoted adipocyte differentiation. Intriguingly, ChREBP-constitutive-active ChREBP expression induced PPARγ activity in a fatty acid synthase-dependent manner and by trans-activating the PPARγ ligand-binding domain. Reducing endogenous ChREBP activity by either small interfering RNA-mediated depletion, exposure to low-glucose concentrations, or expressing a dominant-negative ChREBP impaired differentiation. In adipocytes, ChREBP regulated the expression of PPARγ target genes, in particular those involved in thermogenesis, similar to synthetic PPARγ ligands. In summary, our data suggest that ChREBP controls the generation of endogenous fatty acid species that activate PPARγ. Thus, increasing ChREBP activity in adipose tissue by therapeutic interventions may promote insulin sensitivity through PPARγ.
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Nicole
authors.initials: N
authors.lastname: Witte
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Matthias
authors.initials: M
authors.lastname: Muenzner
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Janita
authors.initials: J
authors.lastname: Rietscher
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Miriam
authors.initials: M
authors.lastname: Knauer
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Steffi
authors.initials: S
authors.lastname: Heidenreich
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Alli M
authors.initials: AM
authors.lastname: Nuotio-Antar
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Franziska A
authors.initials: FA
authors.lastname: Graef
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Ronja
authors.initials: R
authors.lastname: Fedders
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tolkachov
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Isabel
authors.initials: I
authors.lastname: Goehring
authors.affiliation: Charité University School of Medicine (N.W., M.M., J.R., M.K., S.H., F.A.G., R.F., A.T., I.G., M.S.), Institute of Pharmacology, Center for Cardiovascular Research, Berlin 10115, Germany; and Department of Pediatrics (A.M.N.-A.), Baylor College of Medicine, Children's Nutritional Research Center, Houston, Texas 77030.
authors.forename: Michael
authors.initials: M
authors.lastname: Schupp
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002454:Cell Differentiation; D002460:Cell Line; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D050155:Lipogenesis; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D047495:PPAR gamma; D020033:Protein Isoforms; D014157:Transcription Factors; D005947:Glucose