Accessibility navigation


Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety

Moir, L., Bochukova, E. G., Dumbell, R., Banks, G., Bains, R. S., Nolan, P. M., Scudamore, C., Simon, M., Watson, K. A., Keogh, J., Henning, E., Hendricks, A., O'Rahilly, S., Barroso, I., UK10K, C., Sullivan, A. E., Bersten, D. C., Whitelaw, M. L., Kirsch, S., Bentley, E. , Farooqi, I. S. and Cox, R. D. (2017) Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety. Molecular Metabolism, 6 (11). pp. 1419-1428. ISSN 2212-8778

[img]
Preview
Text (Open Access) - Published Version
· Available under License Creative Commons Attribution.
· Please see our End User Agreement before downloading.

3MB

It is advisable to refer to the publisher's version if you intend to cite from this work. See Guidance on citing.

To link to this item DOI: 10.1016/j.molmet.2017.08.006

Abstract/Summary

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.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:72833
Publisher:Elsevier

Downloads

Downloads per month over past year

University Staff: Request a correction | Centaur Editors: Update this record

Page navigation