title: Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis.
abstract: Obesity has tremendous impact on the health systems. Its epigenetic bases are unclear. MacroH2A1 is a variant of histone H2A, present in two alternatively exon-spliced isoforms macroH2A1.1 and macroH2A1.2, regulating cell plasticity and proliferation, during pluripotency and tumorigenesis. Their role in adipose tissue plasticity is unknown.
  
  
  
  Here, we show evidence that macroH2A1.1 protein levels in the visceral adipose tissue of obese humans positively correlate with BMI, while macroH2A1.2 is nearly absent. We thus introduced a constitutive GFP-tagged transgene for macroH2A1.2 in mice, and we characterized their metabolic health upon being fed a standard chow diet or a high fat diet. Despite unchanged food intake, these mice exhibit lower adipose mass and improved glucose metabolism both under a chow and an obesogenic diet. In the latter regimen, transgenic mice display smaller pancreatic islets and significantly less inflammation. MacroH2A1.2 overexpression in the mouse adipose tissue induced dramatic changes in the transcript levels of key adipogenic genes; genomic analyses comparing pre-adipocytes to mature adipocytes uncovered only minor changes in macroH2A1.2 genomic distribution upon adipogenic differentiation and suggested differential cooperation with transcription factors. MacroH2A1.2 overexpression markedly inhibited adipogenesis, while overexpression of macroH2A1.1 had opposite effects.
  
  
  
  MacroH2A1.2 is an unprecedented chromatin component powerfully promoting metabolic health by modulating anti-adipogenic transcriptional networks in the differentiating adipose tissue. Strategies aiming at enhancing macroH2A1.2 expression might counteract excessive adiposity in humans.
authors: Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, 71013 San Giovanni Rotondo, Italy.
authors: Valerio
authors: V
authors: Pazienza
authors: Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, 71013 San Giovanni Rotondo, Italy.
authors: Concetta
authors: C
authors: Panebianco
authors: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy ; Department of Legal, Society and Sport Sciences, University of Palermo, 90133 Palermo, Italy ; Euro-Mediterranean Institute of Science and Technology (IEMEST), 90146 Palermo, Italy.
authors: Francesca
authors: F
authors: Rappa
authors: Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, 84081 Baronissi, SA Italy.
authors: Domenico
authors: D
authors: Memoli
authors: Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, 71013 San Giovanni Rotondo, Italy ; Institute for Liver and Digestive Health, University College London (UCL), Royal Free Hospital, London, NW3 2PF UK.
authors: Michela
authors: M
authors: Borghesan
authors: Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, 71013 San Giovanni Rotondo, Italy.
authors: Sara
authors: S
authors: Cannito
authors: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 5650871 Japan.
authors: Asami
authors: A
authors: Oji
authors: Institute for Liver and Digestive Health, University College London (UCL), Royal Free Hospital, London, NW3 2PF UK.
authors: Giuseppe
authors: G
authors: Mazza
authors: Centre for HPB Surgery and Liver Transplantation, Royal Free Hospital, London, NW3 2QG UK.
authors: Domenico
authors: D
authors: Tamburrino
authors: Centre for HPB Surgery and Liver Transplantation, Royal Free Hospital, London, NW3 2QG UK.
authors: Giuseppe
authors: G
authors: Fusai
authors: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy ; Euro-Mediterranean Institute of Science and Technology (IEMEST), 90146 Palermo, Italy.
authors: Rosario
authors: R
authors: Barone
authors: Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), 00015 Monterotondo, Italy.
authors: Giulia
authors: G
authors: Bolasco
authors: Departament de Bioquimica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), and CIBER Fisiopatologia de la Obesidad y Nutricion, University of Barcelona, Barcelona, 08007 Spain ; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN) ISCIII, Madrid, Spain.
authors: Francesc
authors: F
authors: Villarroya
authors: Departament de Bioquimica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), and CIBER Fisiopatologia de la Obesidad y Nutricion, University of Barcelona, Barcelona, 08007 Spain ; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN) ISCIII, Madrid, Spain.
authors: Joan
authors: J
authors: Villarroya
authors: Faculty of Medicine, Tottori University, Yonago, 683-8503 Japan.
authors: Kiyotaka
authors: K
authors: Hatsuzawa
authors: Department of Experimental Biomedicine and Clinical Neurosciences, Section of Human Anatomy, University of Palermo, 90127 Palermo, Italy ; Euro-Mediterranean Institute of Science and Technology (IEMEST), 90146 Palermo, Italy.
authors: Francesco
authors: F
authors: Cappello
authors: Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry 'Schola Medica Salernitana', University of Salerno, 84081 Baronissi, SA Italy.
authors: Roberta
authors: R
authors: Tarallo
authors: Faculty of Medicine, Tottori University, Yonago, 683-8503 Japan ; The Institute of Medical Sciences, University of Tokyo, Tokyo, 108-8639 Japan.
authors: Tomoko
authors: T
authors: Nakanishi
authors: Gastroenterology Unit, IRCCS "Casa Sollievo della Sofferenza" Hospital, 71013 San Giovanni Rotondo, Italy ; Euro-Mediterranean Institute of Science and Technology (IEMEST), 90146 Palermo, Italy ; Institute for Liver and Digestive Health, University College London (UCL), Royal Free Hospital, London, NW3 2PF UK ; Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne's University Hospital, Brno, 656 91 Czech Republic.
authors: Manlio
authors: M
authors: Vinciguerra
mesh_terms: D050156:Adipogenesis; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D015992:Body Mass Index; D002454:Cell Differentiation; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D005951:Glucose Tolerance Test; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000473:pathology; D060847:Metabolic Engineering; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology; D010641:Phenotype; D012867:Skin / Q000473:pathology; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D007328:Insulin; D000071256:Uncoupling Protein 1; C120756:macroH2A histone
keywords: Adipose tissue; Histone variants; Obesity; macroh2a1.2