Somitogenesis is regulated by a molecular oscillator which drives dynamic gene expression within the PSM with a periodicity tightly coupled to somite formation. Previous mathematical models that invoke the mechanism of delayed negative feedback predict the oscillation period depends on the sum of delays in negative-feedback loops and the inhibitor half-lives. We develop a model to explore the possibility positive feedback also plays a role. The model predicts increasing the half-life of the positive regulator, Notch intracellular domain (NICD), can lead to elevated NICD levels and an increase in the oscillation period. To test this, we investigate a phenotype induced by various small molecule inhibitors in which the clock is slowed. We observe elevated levels and prolonged half-life of NICD. Reducing NICD production rescues these effects. These data provide the first indication tight control of the turnover of positive as well as negative regulators of the clock determines its periodicity.
Animal experimentation: This study was performed under a home office license issued to Dr Kim Dale and under the regulations of the home office Animal Welfare ACT. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of Dundee. The protocol was approved by the ethical committee of the University of Dundee. Every effort was made to minimize suffering.
© 2015, Wiedermann et al.
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Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female Ctrp10 knockout (KO) mice show rapid weight gain. Despite pronounced obesity, Ctrp10 KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologs in humans also shows sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.
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