Functional identity of hypothalamic melanocortin neurons depends on Tbx3
Open accessAbstract
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.
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TBX3 is critically involved in pluripotency maintenance and lineage-specific exit from the pluripotency circuitry in mouse embryonic stem cells.
“Finally, TBX3 is not only critically involved in pluripotency maintenance but also in lineage-specific exit from the pluripotency circuitry in mouse embryonic stem cells [11–17].”
From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [14]
The Results section reports that TBX3 loss impairs maturation of hypothalamic neurons derived from human embryonic stem cells; the Discussion also links Tbx3 generally to differentiation and cell-fate commitment. Neither passage addresses pluripotency maintenance or lineage-specific exit from pluripotency circuitry in mouse embryonic stem cells (searched: pluripotency, mouse embryonic stem cells, lineage-specific exit). (LLM, conf=0.72)
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“TBX3 has been implicated in human diseases including ulnar mammary syndrome, rheumatoid arthritis, obesity and cancer (Frank et al., 2013; Quarta et al., 2019; Sardar et al., 2019; Willmer et al., 2017).”
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POMC Neurons Dysfunction in Diet-induced Metabolic Disease: Hallmark or Mechanism of Disease?
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Ontogenetic rules for the molecular diversification of hypothalamic neurons
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Molecular control of the development of hypothalamic neurons involved in metabolic regulation
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Murine neuronatin deficiency is associated with a hypervariable food intake and bimodal obesity
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Beyond satiety: unraveling the complex roles of POMC neurons in behavior and metabolism
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Control of tuberal hypothalamic development and its implications in metabolic disorders
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The expanding landscape of genetic causes of obesity
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Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity
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TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration
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Adenosine signaling in glia modulates metabolic state-dependent behavior in Drosophila
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Self-citationA new era in childhood obesity
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POMC neuron METTL14/m6A/YTHDC1/YTHDF2 pathways safeguard energy balance, body weight, and metabolism
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Ontogenesis of Hypothalamic Neurons in Mammals
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Loss of Tbx3 in Mouse Eye Causes Retinal Angiogenesis Defects Reminiscent of Human Disease
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Self-citationCan brain neurons change identity? Lessons from obesity
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Genotypic Variations Associated with Changes in Body Mass in Response to Endurance Training
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Adenosine signaling in glia modulates metabolic state-dependent behavior in DrosophilaPreprint
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- Authors
- Quarta, C., Fisette, A., Xu, Y., Colldén, G., Legutko, B., Tseng, Y.-T., Reim, A., Wierer, M., De Rosa, M. C., Klaus, V., Rausch, R., Thaker, V. V., Graf, E., Strom, T. M., Poher, A.-L., Gruber, T., Le Thuc, O., Cebrian-Serrano, A., Kabra, D., Bellocchio, L., Woods, S. C., Pflugfelder, G. O., Nogueiras, R., Zeltser, L., Grunwald Kadow, I. C., Moon, A., García-Cáceres, C., Mann, M., Treier, M., Doege, C. A., & Tschöp, M. H.
- Affiliations
- Université de Bordeaux (FR)
- Helmholtz Munich (DE)
- Max Delbrück Center (DE)
- Max Planck Institute of Biochemistry (DE)
- Columbia University Irving Medical Center (US)
- University of Cincinnati (US)
- Johannes Gutenberg University Mainz (DE)
- Universidade de Santiago de Compostela (ES)
- Geisinger Medical Center (US)
- Corresponding author
- Tschöp, Matthias H.
- ORCID
- Quarta, Carmelo
- Fisette, Alexandre
- Xu, Yanjun
- Colldén, Gustav
- Tseng, Yu-Ting
- Reim, Alexander
- Wierer, Michael
- Thaker, Vidhu V.
- Graf, Elisabeth
- Poher, Anne-Laure
- Gruber, Tim
- Cebrian-Serrano, Alberto
- Bellocchio, Luigi
- Woods, Stephen C.
- Nogueiras, Rubén
- Zeltser, Lori
- Moon, Anne
- Mann, Matthias
- Treier, Mathias
- Doege, Claudia A.
- Tschöp, Matthias H.
- Venue
- Nature Metabolism
- Published
- 2019-01-28
- Volume
- 1
- Issue
- 2
- Pages
- 222-235
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC8291379
- OpenAlex
- W2915007177
- Cited by
- 54
- References
- 81
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 10 · 2023: 2 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 5
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- National Institutes of Health (P40OD018537)
- Canadian Institutes of Health Research (152588)
- National Human Genome Research Institute (U54HG006542)
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK110539, R01DK052431, R01DK110113, P30DK026687)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- TBX3, hypothalamic neurons, melanocortin system, energy balance, body weight regulation, obesity, embryonic stem cell differentiation, Drosophila melanogaster, transcription factors
- MeSH terms
- Animals, Body Weight, Energy Metabolism, Hypothalamus, Mice, Inbred C57BL, Neurons, Pro-Opiomelanocortin, RNA, Messenger, T-Box Domain Proteins, Gene Expression Profiling, Green Fluorescent Proteins, Mice, Melanocortins, Agouti-Related Protein
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