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Hexim1, a Novel Regulator of Leptin Function, Modulates Obesity and Glucose Disposal.

Authors
  • Dhar-Mascareno, Manya1
  • Ramirez, Susan N1
  • Rozenberg, Inna1
  • Rouille, Yves1
  • Kral, John G1
  • Mascareno, Eduardo J1
  • 1 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. , (France)
Type
Published Article
Journal
Molecular Endocrinology
Publisher
The Endocrine Society
Publication Date
Mar 01, 2016
Volume
30
Issue
3
Pages
314–324
Identifiers
DOI: 10.1210/me.2015-1211
PMID: 26859361
Source
Medline
License
Unknown

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.

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