title: Hexim1, a Novel Regulator of Leptin Function, Modulates Obesity and Glucose Disposal.
abstract: Leptin triggers signaling events with significant transcriptional responses that are essential to metabolic processes affecting obesity and glucose disposal. We asked whether hexamethylene bis-acetamide inducible-1 (Hexim1), an inhibitor of RNA II polymerase-dependent transcription elongation, regulates leptin-Janus kinase 2 signaling axis in the hypothalamus. We subjected C57BL6 Hexim1 heterozygous (HT) mice to high-fat diet and when compared with wild type, HT mice were resistant to high-fat diet-induced weight gain and remain insulin sensitive. HT mice exhibited increased leptin-pY(705)Stat3 signaling in the hypothalamus, with normal adipocyte size, increased type I oxidative muscle fiber density, and enhanced glucose transporter 4 expression. We also observed that normal Hexim1 protein level is required to facilitate the expression of CCAAT/enhancer-binding proteins (C/EBPs) required for adipogenesis and inducible suppressor of cytokine signaling 3 (SOCS) expression. Further support on the role of Hexim1 regulating C/EBPs during adipocyte differentiation was shown when HT 3T3L1 fibroblasts failed to undergo adipogenesis. Hexim1 selectively modulates leptin-mediated signal transduction pathways in the hypothalamus, the expression of C/EBPs and peroxisome proliferator-activated receptor-γ (PPAR γ) in skeletal muscle and adipose tissue during the adaptation to metabolic stress. We postulate that Hexim1 might be a novel factor involved in maintaining whole-body energy balance.
authors: Department of Biological Sciences (M.D.-M., S.N.R.), State University of New York, College at Old Westbury, Old Westbury, New York 11568; Departments of Cell Biology (I.R., E.J.M.) and Surgery, Medicine, and Cell Biology (J.G.K.), State University of New York Downstate Medical Center, Brooklyn, New York 11203; and Institute Pasteur Inserm (Y.R.), Cenre National de la Recherche Scientifique, Center for Infection and Immunity of Lille, UMR8204, U1019, F-59021 Lille, France.
authors: Manya
authors: M
authors: Dhar-Mascareno
authors: Department of Biological Sciences (M.D.-M., S.N.R.), State University of New York, College at Old Westbury, Old Westbury, New York 11568; Departments of Cell Biology (I.R., E.J.M.) and Surgery, Medicine, and Cell Biology (J.G.K.), State University of New York Downstate Medical Center, Brooklyn, New York 11203; and Institute Pasteur Inserm (Y.R.), Cenre National de la Recherche Scientifique, Center for Infection and Immunity of Lille, UMR8204, U1019, F-59021 Lille, France.
authors: Susan N
authors: SN
authors: Ramirez
authors: Department of Biological Sciences (M.D.-M., S.N.R.), State University of New York, College at Old Westbury, Old Westbury, New York 11568; Departments of Cell Biology (I.R., E.J.M.) and Surgery, Medicine, and Cell Biology (J.G.K.), State University of New York Downstate Medical Center, Brooklyn, New York 11203; and Institute Pasteur Inserm (Y.R.), Cenre National de la Recherche Scientifique, Center for Infection and Immunity of Lille, UMR8204, U1019, F-59021 Lille, France.
authors: Inna
authors: I
authors: Rozenberg
authors: Department of Biological Sciences (M.D.-M., S.N.R.), State University of New York, College at Old Westbury, Old Westbury, New York 11568; Departments of Cell Biology (I.R., E.J.M.) and Surgery, Medicine, and Cell Biology (J.G.K.), State University of New York Downstate Medical Center, Brooklyn, New York 11203; and Institute Pasteur Inserm (Y.R.), Cenre National de la Recherche Scientifique, Center for Infection and Immunity of Lille, UMR8204, U1019, F-59021 Lille, France.
authors: Yves
authors: Y
authors: Rouille
authors: Department of Biological Sciences (M.D.-M., S.N.R.), State University of New York, College at Old Westbury, Old Westbury, New York 11568; Departments of Cell Biology (I.R., E.J.M.) and Surgery, Medicine, and Cell Biology (J.G.K.), State University of New York Downstate Medical Center, Brooklyn, New York 11203; and Institute Pasteur Inserm (Y.R.), Cenre National de la Recherche Scientifique, Center for Infection and Immunity of Lille, UMR8204, U1019, F-59021 Lille, France.
authors: John G
authors: JG
authors: Kral
authors: Department of Biological Sciences (M.D.-M., S.N.R.), State University of New York, College at Old Westbury, Old Westbury, New York 11568; Departments of Cell Biology (I.R., E.J.M.) and Surgery, Medicine, and Cell Biology (J.G.K.), State University of New York Downstate Medical Center, Brooklyn, New York 11203; and Institute Pasteur Inserm (Y.R.), Cenre National de la Recherche Scientifique, Center for Infection and Immunity of Lille, UMR8204, U1019, F-59021 Lille, France.
authors: Eduardo J
authors: EJ
authors: Mascareno
mesh_terms: D016475:3T3 Cells; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D057809:HEK293 Cells; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D015430:Weight Gain
chemical_list: D051275:Glucose Transporter Type 4; C118642:Hexim1 protein, mouse; D020738:Leptin; D016601:RNA-Binding Proteins; D050796:STAT3 Transcription Factor; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D019000:Phosphotyrosine; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D005947:Glucose