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
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
