A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome

Elena G. Bochukova; Katherine Lawler; Sophie Croizier; Julia M. Keogh; Nisha Patel; Garth Strohbehn; Kitty K. Lo; Jack Humphrey; Anita Hokken-Koelega; Layla Damen; Stephany Donze; Sebastien G. Bouret; Vincent Plagnol; I. Sadaf Farooqi

Cell Reports (Mar 2018)

A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome

Elena G. Bochukova,
Katherine Lawler,
Sophie Croizier,
Julia M. Keogh,
Nisha Patel,
Garth Strohbehn,
Kitty K. Lo,
Jack Humphrey,
Anita Hokken-Koelega,
Layla Damen,
Stephany Donze,
Sebastien G. Bouret,
Vincent Plagnol,
I. Sadaf Farooqi

Affiliations

Elena G. Bochukova: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK; The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; Corresponding author
Katherine Lawler: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
Sophie Croizier: The Saban Research Institute, Developmental Neuroscience Program, and Diabetes and Obesity Program, Children’s Hospital Los Angeles, Center for Endocrinology, Diabetes and Metabolism, University of Southern California, Los Angeles, CA 90027, USA; Inserm, Jean-Pierre Aubert Research Center, U1172, University Lille 2, Lille, 59045, France; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
Julia M. Keogh: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
Nisha Patel: The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
Garth Strohbehn: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
Kitty K. Lo: University College London Genetics Institute (UGI), Department of Genetics, Environment and Evolution, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK
Jack Humphrey: University College London Genetics Institute (UGI), Department of Genetics, Environment and Evolution, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK; Department of Neurodegenerative Disease, University College London Institute of Neurology, London, WC1N 3BG, UK
Anita Hokken-Koelega: Erasmus University Medical Center, Rotterdam, the Netherlands; Dutch Growth Research Foundation, Rotterdam, the Netherlands
Layla Damen: Erasmus University Medical Center, Rotterdam, the Netherlands; Dutch Growth Research Foundation, Rotterdam, the Netherlands
Stephany Donze: Erasmus University Medical Center, Rotterdam, the Netherlands; Dutch Growth Research Foundation, Rotterdam, the Netherlands
Sebastien G. Bouret: The Saban Research Institute, Developmental Neuroscience Program, and Diabetes and Obesity Program, Children’s Hospital Los Angeles, Center for Endocrinology, Diabetes and Metabolism, University of Southern California, Los Angeles, CA 90027, USA; Inserm, Jean-Pierre Aubert Research Center, U1172, University Lille 2, Lille, 59045, France
Vincent Plagnol: University College London Genetics Institute (UGI), Department of Genetics, Environment and Evolution, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK
I. Sadaf Farooqi: University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK; Corresponding author

Journal volume & issue: Vol. 22, no. 13
pp. 3401 – 3408

Abstract

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Summary: Transcriptional analysis of brain tissue from people with molecularly defined causes of obesity may highlight disease mechanisms and therapeutic targets. We performed RNA sequencing of hypothalamus from individuals with Prader-Willi syndrome (PWS), a genetic obesity syndrome characterized by severe hyperphagia. We found that upregulated genes overlap with the transcriptome of mouse Agrp neurons that signal hunger, while downregulated genes overlap with the expression profile of Pomc neurons activated by feeding. Downregulated genes are expressed mainly in neuronal cells and contribute to neurogenesis, neurotransmitter release, and synaptic plasticity, while upregulated, predominantly microglial genes are involved in inflammatory responses. This transcriptional signature may be mediated by reduced brain-derived neurotrophic factor expression. Additionally, we implicate disruption of alternative splicing as a potential molecular mechanism underlying neuronal dysfunction in PWS. Transcriptomic analysis of the human hypothalamus may identify neural mechanisms involved in energy homeostasis and potential therapeutic targets for weight loss. : Prader-Willi syndrome (PWS) is a genetic obesity syndrome. Bochukova et al. report gene expression changes in the hypothalamus of people with PWS that support neurodegeneration and neuroinflammation as key processes involved in this condition. Keywords: hypothalamus, Prader-Willi syndrome, BDNF, Agrp, obesity, SNORD116

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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