Functional identity of hypothalamic melanocortin neurons depends on Tbx3
Authors: Maria Caterina De Rosa
Alberto Cebrian-Serrano
Carmelo Quarta
Yanjun Xu
Ophélia Le Thuc
Matthias H Tschöp
Cristina García-Cáceres
Ilona C Grunwald Kadow
Luigi Bellocchio
Tim Gruber
Anne-Laure Poher
Michael Wierer
Alexandre Fisette
Gert O Pflugfelder
Beata Legutko
Gustav Colldén
Mathias Treier
Alexander Reim
Stephen C Woods
Rubén Nogueiras
Yu-Ting Tseng
Valentina Klaus
Claudia A Doege
Lori Zeltser
Rick Rausch
Dhiraj Kabra
Anne Moon
Tim M Strom
Vidhu V Thaker
Elisabeth Graf
Matthias Mann
Journal: Nature Metabolism (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Hypothalamic neurons; T-box 3; peptidergic identity; energy balance; obesity
Affiliations: Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany., German Center for Diabetes Research (DZD), Neuherberg, Germany., INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, Bordeaux, France., University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, Bordeaux, France., Division of Metabolic Diseases, Technische Universität München, Munich, Germany., Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Charité-Universitätsmedizin Berlin, Berlin, Germany., Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany., Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Department of Pediatrics, Columbia University, New York, NY, USA., Naomi Berrie Diabetes Center, Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, NY, USA., Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany., INSERM U1215, NeuroCentre Magendie, Bordeaux, France., Université de Bordeaux, NeuroCentre Magendie, Bordeaux, France., University of Cincinnati College of Medicine, Department of Psychiatry and Behavioral Neuroscience, Metabolic Diseases Institute, Cincinnati, OH, USA., Institute of Developmental and Neurobiology. Johannes Gutenberg-University, Mainz, Germany., Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain., CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain., Naomi Berrie Diabetes Center, Columbia Stem Cell Initiative, Department of Pathology and Cell Biology, Columbia University, New York, NY, USA., Technical University of Munich, School of Life Sciences, ZIEL - Institute for Food and Health, Freising, Germany., Department of Molecular and Functional Genomics, Geisinger Clinic, Danville PA, USA., Departments of Pediatrics and Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, USA., Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany. ., German Center for Diabetes Research (DZD), Neuherberg, Germany. ., Division of Metabolic Diseases, Technische Universität München, Munich, Germany. .

Abstract:  Heterogeneous populations of hypothalamic neurons orchestrate energy balance via the release of specific signatures of neuropeptides. However, how specific intracellular machinery controls peptidergic identities and function of individual hypothalamic neurons remains largely unknown. The transcription factor T-box 3 (Tbx3) is expressed in hypothalamic neurons sensing and governing energy status, whereas human TBX3 haploinsufficiency has been linked with obesity. Here, we demonstrate that loss of Tbx3 function in hypothalamic neurons causes weight gain and other metabolic disturbances by disrupting both the peptidergic identity and plasticity of Pomc/Cart and Agrp/Npy neurons. These alterations are observed after loss of Tbx3 in both immature hypothalamic neurons and terminally differentiated mouse neurons. We further establish the importance of Tbx3 for body weight regulation in Drosophila melanogaster and show that TBX3 is implicated in the differentiation of human embryonic stem cells into hypothalamic Pomc neurons. Our data indicate that Tbx3 directs the terminal specification of neurons as functional components of the melanocortin system and is required for maintaining their peptidergic identity. In summary, we report the discovery of a key mechanistic process underlying the functional heterogeneity of hypothalamic neurons governing body weight and systemic metabolism. 

Retracted: No

PubPeer comments:
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