Effect of Exercise on Photoperiod-Regulated Hypothalamic Gene Expression and Peripheral Hormones in the Seasonal Dwarf Hamster Phodopus sungorus

Acknowledgments: Many thanks to Dana Wilson, Susan Hay, David Brown and Vivienne Buchan at RINH, Siegrid Hilken and Esther Lipokatic-Takacs at UVMH for the excellent technical support and advice provided. Many thanks are due to Claus Mayer of Biomathematics, Statistics Scotland for assistance with the statistical analysis of data. Author Contributions: Conceived and designed the experiments: IP SS FS PB. Performed the experiments: IP RD FS. Analyzed the data: IP RD FS SS PB. Wrote the paper: PB SS FS IP.Peer reviewedPublisher PD

Modelling the genetic aetiology of complex disease: human-mouse conservation of noncoding features and disease-associated loci

Understanding the genetic aetiology of loci associated with a disease is crucial for developing preventative measures and effective treatments. Mouse models are used extensively to understand human pathobiology and mechanistic functions of disease-associated loci. However, the utility of mouse models is limited in part by evolutionary divergence in transcription regulation for pathways of interest. Here, we summarize the alignment of genomic (exonic and multi-cell regulatory) annotations alongside Mendelian and complex disease-associated variant sites between humans and mice. Our results highlight the importance of understanding evolutionary divergence in transcription regulation when interpreting functional studies using mice as models for human disease variants

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-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

The effect of running wheel activity on organ mass.

<p>(A) Liver, (B) heart, (C) kidney, (D) paired testes, (E) right epididymal fat pad of adult male Siberian hamsters after 8 (filled bars) or 16 week (open bars) exposure to long day (LD) or short day (SD) photoperiod with (RW) or without (C) a running wheel (n = 6 per group 8 weeks or 6–9 per group 16 weeks). Relevant significant differences are shown *P<0.05, **P<0.01, ***P<0.001.</p

Summary of the physiological, metabolic and hypothalamic gene expression changes in exercising Siberian hamsters with free access to a running wheel compared to sedentary Siberian hamsters in short photoperiod.

<p>↑↓ indicates a significant elevated or decreased value, ↔ indicates no change or the change is not significant. The suffix a, b or c indicates an overall significant effect (P<0.05 or less) for photoperiod (a), activity (b) or interaction between photoperiod and activity (c).</p

The effect of running wheel activity on body weight.

<p>A) Mean body mass (g) of adult male Siberian hamsters during an 8 week exposure to short day (SD) or long day (LD) photoperiod with or without access to a running wheel (n = 7 per group). * SD-C significantly different vs SD-RW (P<0.05 or lower). B) 16 week photoperiod exposure (n = 6–9 per group) ^a SD-C significantly different to the other 3 groups (P<0.05 or lower). # Significantly different from LD-RW group (P<0.05).</p

Quantification of somatotropin release-inhibiting factor (<i>Srif</i>) mRNA expression in the hypothalamic arcuate nucleus (ARC).

<p>Adult male Siberian hamsters were exposed to long day (LD) or short day (SD) photoperiod or with (RW) or without (C) a running wheel for 8 weeks (n = 5–6 in each group). Values are means ± SEM. The SD-C group was set to 100% expression value and other treatment values were calculated accordingly ( ###P<0.001 with respect to an overall effect of photoperiod; *; P<0.05 with respect to post-hoc analysis between groups).</p

Messenger RNA expression of photoperiod-regulated genes in the ventricular ependymal cells.

<p>Quantification of (A) Vimentin and (B) G-protein-coupled receptor 50 (<i>Gpr50</i>) mRNA expression. Adult male Siberian hamsters were exposed to long day (LD) photoperiod or short day (SD) photoperiod or with (RW) or without (C) a running wheel for 8 weeks (n = 6–7 in each group). The LD-C group was set to 100% expression value and other treatment values were calculated accordingly. Results show means ± SEM (*P<0.05).</p

Messenger RNA expression of genes involved in homeostatic mechanisms of appetite and energy balance.

<p>Quantification of (A) agouti-related protein (A<i>grp</i>), (B) neuropeptide Y (N<i>py</i>), (C) cocaine- and amphetamine-regulated transcript (C<i>art</i>) and (D) proopiomelanocortin (P<i>omc</i>) mRNA expression in the hypothalamic arcuate nucleus (ARC) of adult male Siberian hamsters after 8 weeks exposure to long day (LD) photoperiod or short day (SD) photoperiod with (RW) or without (C) a running wheel (N = 6 in each group). (E) Proopiomelanocortin (<i>Pomc</i>) mRNA expression in the hypothalamic arcuate nucleus (ARC) after 12 weeks exposure to long day (LD) photoperiod or short day (SD) photoperiod or with (RW) or without (C) a running wheel (n = 5–6 in each group). The LD-C group was set to 100% expression value and other treatment values were calculated accordingly. Results show means+SEM (##P<0.01, #P<0.05 with respect to an overall effect of photoperiod; *P<0.05, **P<0.01, ***P<0.001, with respect to post-hoc analysis of differences between groups).</p