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

Lee Moir,Kimberly A Watson,Rasneer S Bains,Gareth Banks,Michelle Simon,Inês Barroso,Roger D Cox,Elana Henning,Elena G Bochukova,Adrienne E Sullivan,David C Bersten,Susan Kirsch,Murray L Whitelaw,Patrick M Nolan,Elizabeth Bentley,Rebecca Dumbell,I Sadaf Farooqi,Stephen O’rahilly ,Cheryl L Scudamore ,Julia M Keogh ,Audrey E Hendricks

doi:10.1016/j.molmet.2017.08.006

Abstract

ObjectiveGenetic studies in obese rodents and humans can provide novel insights into the mechanisms involved in energy homeostasis. MethodsIn 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. ResultsWe 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. ConclusionsOTP 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.

Highlights

The development of neuroendocrine cell lineages in the hypothalamus requires a number of transcription factors including orthopedia homeobox (OTP) and single-minded-homology 1 (SIM1)
Obesity in a mutagenized mouse model maps to the orthopedia homeobox (Otp) gene In this study, we identified a point mutation in Otp in an obese male mouse (61.4 g at 14-weeks) emerging from a high throughput dominant mouse N-ethyl-N-nitrosourea (ENU) mutagenesis screen
We found that agouti-related peptide (Agrp) mRNA levels were reduced at 4-weeks but normalized by 8- and 10-weeks, while pro-opiomelanocortin (Pomc) expression trended to elevation (p 1⁄4 0.056 ManneWhitney) at 10 weeks (Figure 3B), suggesting that the hyperphagia of these mice may be driven by mechanisms downstream of these signals; there were no differences in corticotrophin-releasing hormone (Crh), leptin receptor (Lepr), and melanocortin 4 receptor (Mc4r) expression

Summary

Introduction

The development of neuroendocrine cell lineages in the hypothalamus requires a number of transcription factors including orthopedia homeobox (OTP) and single-minded-homology 1 (SIM1). With the exception of the arcuate nucleus (ARC), where SIM1 is not found, OTP and SIM1 are co-expressed at the same time and in the same cells [1]. Germline haploinsufficiency of Sim in mice and loss of function mutations in SIM1 in humans result in hyperphagic obesity [2e6]. Loss of Sim in mice leads to perinatal death, but haploinsufficient mice are viable and show a reduction in the number of arginine vasopressin (AVP) and oxytocin (OXT) producing neurons in the paraventricular nucleus (PVN) [7]. Disruption of Sim expression in adult mice leads to increased food intake and obesity, suggesting that Sim1’s effects on energy homeostasis are not confined to its role in hypothalamic development [8].

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Conclusion