Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety
Objective: Genetic studies in obese rodents and humans can provide novel insights into the mechanisms involved in energy homeostasis. Methods: In this study, we genetically mapped the chromosomal region underlying the development of severe obesity in a mouse line identified as part of a dominant N-e...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-11-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287781730604X |
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| author | Lee Moir Elena G. Bochukova Rebecca Dumbell Gareth Banks Rasneer S. Bains Patrick M. Nolan Cheryl Scudamore Michelle Simon Kimberly A. Watson Julia Keogh Elana Henning Audrey Hendricks Stephen O'Rahilly Inês Barroso Adrienne E. Sullivan David C. Bersten Murray L. Whitelaw Susan Kirsch Elizabeth Bentley I. Sadaf Farooqi Roger D. Cox |
| author_facet | Lee Moir Elena G. Bochukova Rebecca Dumbell Gareth Banks Rasneer S. Bains Patrick M. Nolan Cheryl Scudamore Michelle Simon Kimberly A. Watson Julia Keogh Elana Henning Audrey Hendricks Stephen O'Rahilly Inês Barroso Adrienne E. Sullivan David C. Bersten Murray L. Whitelaw Susan Kirsch Elizabeth Bentley I. Sadaf Farooqi Roger D. Cox |
| author_sort | Lee Moir |
| collection | DOAJ |
| description | Objective: Genetic studies in obese rodents and humans can provide novel insights into the mechanisms involved in energy homeostasis.
Methods: In this study, we genetically mapped the chromosomal region underlying the development of severe obesity in a mouse line identified as part of a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen. We characterized the metabolic and behavioral phenotype of obese mutant mice and examined changes in hypothalamic gene expression. In humans, we examined genetic data from people with severe early onset obesity.
Results: We identified an obese mouse heterozygous for a missense mutation (pR108W) in orthopedia homeobox (Otp), a homeodomain containing transcription factor required for the development of neuroendocrine cell lineages in the hypothalamus, a region of the brain important in the regulation of energy homeostasis. OtpR108W/+ mice exhibit increased food intake, weight gain, and anxiety when in novel environments or singly housed, phenotypes that may be partially explained by reduced hypothalamic expression of oxytocin and arginine vasopressin. R108W affects the highly conserved homeodomain, impairs DNA binding, and alters transcriptional activity in cells. We sequenced OTP in 2548 people with severe early-onset obesity and found a rare heterozygous loss of function variant in the homeodomain (Q153R) in a patient who also had features of attention deficit disorder.
Conclusions: OTP is involved in mammalian energy homeostasis and behavior and appears to be necessary for the development of hypothalamic neural circuits. Further studies will be needed to investigate the contribution of rare variants in OTP to human energy homeostasis. |
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| format | Article |
| id | doaj.art-9e406993ddb94b1f857c7323c01dc9e0 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-11T08:50:39Z |
| publishDate | 2017-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-9e406993ddb94b1f857c7323c01dc9e02022-12-22T01:14:01ZengElsevierMolecular Metabolism2212-87782017-11-016111419142810.1016/j.molmet.2017.08.006Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxietyLee Moir0Elena G. Bochukova1Rebecca Dumbell2Gareth Banks3Rasneer S. Bains4Patrick M. Nolan5Cheryl Scudamore6Michelle Simon7Kimberly A. Watson8Julia Keogh9Elana Henning10Audrey Hendricks11Stephen O'Rahilly12Inês Barroso13Adrienne E. Sullivan14David C. Bersten15Murray L. Whitelaw16Susan Kirsch17Elizabeth Bentley18I. Sadaf Farooqi19Roger D. Cox20MRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire, OX11 0RD, UKUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UKMRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire, OX11 0RD, UKMRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire, OX11 0RD, UKMRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire, OX11 0RD, UKMRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire, OX11 0RD, UKMRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire, OX11 0RD, UKMRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire, OX11 0RD, UKSchool of Biological Sciences, University of Reading, Reading, Berkshire, UKUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UKUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UKWellcome Trust Sanger Institute, Cambridge, UKUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UKWellcome Trust Sanger Institute, Cambridge, UKDepartment Molecular and Cellular Biology, University of Adelaide, Adelaide, AustraliaDepartment Molecular and Cellular Biology, University of Adelaide, Adelaide, AustraliaUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UKDepartment of Endocrinology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, CanadaMRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire, OX11 0RD, UKUniversity of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Cambridge CB2 0QQ, UKMRC Harwell Institute, Mammalian Genetics Unit and Mary Lyon Centre, Harwell Campus, Oxfordshire, OX11 0RD, UKObjective: Genetic studies in obese rodents and humans can provide novel insights into the mechanisms involved in energy homeostasis. Methods: In this study, we genetically mapped the chromosomal region underlying the development of severe obesity in a mouse line identified as part of a dominant N-ethyl-N-nitrosourea (ENU) mutagenesis screen. We characterized the metabolic and behavioral phenotype of obese mutant mice and examined changes in hypothalamic gene expression. In humans, we examined genetic data from people with severe early onset obesity. Results: We identified an obese mouse heterozygous for a missense mutation (pR108W) in orthopedia homeobox (Otp), a homeodomain containing transcription factor required for the development of neuroendocrine cell lineages in the hypothalamus, a region of the brain important in the regulation of energy homeostasis. OtpR108W/+ mice exhibit increased food intake, weight gain, and anxiety when in novel environments or singly housed, phenotypes that may be partially explained by reduced hypothalamic expression of oxytocin and arginine vasopressin. R108W affects the highly conserved homeodomain, impairs DNA binding, and alters transcriptional activity in cells. We sequenced OTP in 2548 people with severe early-onset obesity and found a rare heterozygous loss of function variant in the homeodomain (Q153R) in a patient who also had features of attention deficit disorder. Conclusions: OTP is involved in mammalian energy homeostasis and behavior and appears to be necessary for the development of hypothalamic neural circuits. Further studies will be needed to investigate the contribution of rare variants in OTP to human energy homeostasis.http://www.sciencedirect.com/science/article/pii/S221287781730604XOTPObesityEnergy balanceMouse modelHuman mutationOxytocinVasopressin |
| spellingShingle | Lee Moir Elena G. Bochukova Rebecca Dumbell Gareth Banks Rasneer S. Bains Patrick M. Nolan Cheryl Scudamore Michelle Simon Kimberly A. Watson Julia Keogh Elana Henning Audrey Hendricks Stephen O'Rahilly Inês Barroso Adrienne E. Sullivan David C. Bersten Murray L. Whitelaw Susan Kirsch Elizabeth Bentley I. Sadaf Farooqi Roger D. Cox Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety Molecular Metabolism OTP Obesity Energy balance Mouse model Human mutation Oxytocin Vasopressin |
| title | Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety |
| title_full | Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety |
| title_fullStr | Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety |
| title_full_unstemmed | Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety |
| title_short | Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety |
| title_sort | disruption of the homeodomain transcription factor orthopedia homeobox otp is associated with obesity and anxiety |
| topic | OTP Obesity Energy balance Mouse model Human mutation Oxytocin Vasopressin |
| url | http://www.sciencedirect.com/science/article/pii/S221287781730604X |
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