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

Moir, L; Bochukova, EG; Dumbell, R; Banks, G; Bains, RS; Nolan, PM; Scudamore, C; Simon, M; Watson, KA; Keogh, J; et al. Moir, L; Bochukova, EG; Dumbell, R; Banks, G; Bains, RS; Nolan, PM; Scudamore, C; Simon, M; Watson, KA; Keogh, J; Henning, E; Hendricks, A; O'Rahilly, S; Barroso, I; UK10K consortium; Sullivan, AE; Bersten, DC; Whitelaw, ML; Kirsch, S; Bentley, E; Farooqi, IS; Cox, RD (2017) Disruption of the homeodomain transcription factor orthopedia homeobox (Otp) is associated with obesity and anxiety. Mol Metab, 6 (11). pp. 1419-1428. ISSN 2212-8778 https://doi.org/10.1016/j.molmet.2017.08.006
SGUL Authors: Jamshidi, Yalda

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Abstract

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
Additional Information: © 2017 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Energy balance, Human mutation, Mouse model, OTP, Obesity, Oxytocin, Vasopressin, OTP, Obesity, Energy balance, Mouse model, Human mutation, Oxytocin, Vasopressin
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Mol Metab
ISSN: 2212-8778
Language: eng
Dates:
DateEvent
November 2017Published
24 August 2017Published Online
1 August 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
WT091310Wellcome Trusthttp://dx.doi.org/10.13039/100004440
MC_U142661184Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MC_U142684173Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
098497/Z/12/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
WT098051Wellcome Trusthttp://dx.doi.org/10.13039/100004440
MRC_MC_UU_12012/5Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 29107289
Web of Science ID: WOS:000419084000008
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/109528
Publisher's version: https://doi.org/10.1016/j.molmet.2017.08.006

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