Developing an evolutionary model for metabolic syndrome: understanding energy sparing adaptations in geothermal populations of stickleback

大多数人类疾病是复杂的，涉及多种基因、环境输入以及患病率随年龄的变化。为了了解这些疾病，临床研究人员经常使用一组与人类疾病相似的特定实验动物（模式生物）。然而，尽管这种方法为了解人类疾病的一些因果突变提供了重大进展，但在如何转化结果方面可能存在局限性。这通常归因于人类和其他动物之间的差异，但也可能是所使用方法的结果。通常，对这类模式生物的实验室研究使环境条件以及实验室系内的遗传变异标准化。这可以简化与“其他条件相同”方法的比较，该方法允许对单个突变进行比较（即，这通常被称为突变模型方法）。然而，正如上面所提到的，许多疾病表现为多种基因、环境和年龄。一种替代传统突变模型方法的新方法现在来自自然界，在某些情况下，进化适应实际上可以类似于人类疾病。特别令人兴奋的是，这样的种群可以更符合人类的生活方式，因为它们经历了环境的变化，并且通常具有多样性的遗传变异。因此，它们对于理解复杂的人类疾病可能特别有效。该项目将利用一组自然种群的鱼类，特别是由于冰岛地热活动而经历温暖栖息地的三刺鱼。这样温暖的栖息地对这些鱼来说是一个独特的挑战，因为更高的温度会提高它们的新陈代谢，包括在猎物有限的冬天。这似乎导致了这些鱼类进化出了“能量节约”的适应性，比如脂肪沉积增加、葡萄糖耐受性增强和食欲增加。这可以被认为类似于人类的代谢综合征，但尚不清楚决定这些变化的潜在机制，以及是否涉及更广泛的特征。要确定这个系统作为人类疾病模型的效用，还需要更深入的研究，但如果这些鱼也进化出了减轻这些特征的负面影响的能力，那就特别有价值了。因此，我们的目标是确定这些鱼的身体组成是如何使用一个综合的方法来确定遗传、表观遗传和环境线索的。这种方法应该更接近于特征在自然界中是如何决定的，并导致对其机制的准确见解。我们还将进一步评估地热种群和环境种群之间的代谢差异，包括葡萄糖和胰岛素耐受性。最后，我们将研究代谢综合征的预期负面影响是否与棘鱼的相关特征有关。具体来说，我们将寻找非酒精性脂肪性肝病的迹象，并测试地热鱼的血液中甘油三酯和胆固醇的浓度是否会出现（这将在体脂水平较高的情况下出现）。我们预测地热鱼将显示出减轻这些负面影响的迹象，如果得到支持，它可以为进一步了解甚至治疗人类提供基础。

Most human disorders are complex and involve a multitude of genes, environmental inputs, and change in prevalence with age. To understand such disorders clinical researchers often use a specific set of lab animals (model organisms) that display similarity to human disease. However, while this approach has provided major advances for understanding some of the causal mutations underlying human disease there can be limitations in terms of how translatable results are. This is often attributed to differences between humans and other animals but it may also be the result of the approach used. Normally, lab-based research on such model organisms standardizes environmental conditions, as well as genetic variation within a lab line. This can simplify comparisons with an 'all else being equal' approach that allows for single mutations to be compared (i.e. this is often referred to as the mutant model approach). However, as mentioned above, many diseases manifest themselves from a multitude of genes, environments, and age. An emerging alternative to the traditional mutant model approach is now arriving from nature where in some cases evolutionary adaptations can actually resemble human disease. What is particularly exciting in that such populations can be more in line with how humans live, in that they experience environmental variation, and often have a diversity of genetic variation. Thus, they could be particularly effective for understanding complex human disease. This project will take advantage of a natural set of populations of fish, specifically threespine sticklebacks experiencing warmed habitats as a result of geothermal activity in Iceland. Such warmed habitats present a unique challenge to these fish as the higher temperature raises their metabolism, including in winter when prey are limited. This appears to have caused 'energy-sparing' adaptations to evolve in these fish, such as increased fat deposition, indications of glucose tolerance, and higher appetites. This can be considered to resemble metabolic syndrome in humans, but it is unclear what underlying mechanisms determine these changes, and whether a wider suite of traits are involved. To determine the utility of this system as a model for human disease will require deeper investigation, but could be especially valuable if these fish have also evolved the mitigate the negative effects of these traits. Therefore, we will aim to ascertain how the body composition of these fish is determined using a comprehensive approach that accounts for genetic, epigenetic, and environmental cues. This approach should more closely match how traits are determined in nature and lead to accurate insights about their mechanisms. We will also assess further aspects of the metabolic divergence between geothermal and ambient populations of stickleback, including glucose and insulin tolerance. Lastly, we will examine whether the expected negative effects of metabolic syndrome occur with associated traits in sticklebacks. Specifically, we will look for signs of non-alcoholic fatty liver disease, and test whether blood concentrations of triglycerides and cholesterol occur in geothermal fish (which would be expected to occur with higher levels of body fat). We predict that geothermal fish will show signs of mitigating these negative effects, and if supported it could provide the basis for further insight and even therapies for humans.