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

开发代谢综合征的进化模型：了解刺鱼地热种群的能量节约适应

• 批准号: BB/W002515/1
• 负责人: Kevin Parsons
• 金额: $ 98.69万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW002515%2F1
• 关键词: Developing; evolutionary; model; metabolic; syndrome

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.

大多数人类疾病是复杂的，涉及大量的基因，环境输入，并随着年龄的变化而发生变化。为了了解这些疾病，临床研究人员经常使用一组特定的实验室动物（模式生物），这些动物与人类疾病相似。然而，虽然这种方法为理解人类疾病的一些因果突变提供了重大进展，但在结果的可翻译性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。通常情况下，基于实验室的研究，这种模式生物的环境条件，以及遗传变异的实验室线。这可以简化与允许比较单个突变的“其他条件相同”方法的比较（即，这通常被称为突变模型方法）。然而，如上所述，许多疾病的表现来自于大量的基因、环境和年龄。一种新兴的替代传统突变模型的方法现在来自自然界，在某些情况下，进化适应实际上类似于人类疾病。特别令人兴奋的是，这些人群可以更符合人类的生活方式，因为他们经历了环境变化，并且通常具有遗传变异的多样性。因此，它们可能对理解复杂的人类疾病特别有效。该项目将利用一组自然的鱼类种群，特别是由于冰岛地热活动而经历温暖栖息地的三刺鱼。这种温暖的栖息地对这些鱼提出了独特的挑战，因为较高的温度会提高它们的新陈代谢，包括在猎物有限的冬季。这似乎导致了这些鱼进化出“节省能量”的适应性，例如增加脂肪沉积，葡萄糖耐受性的迹象和更高的食欲。这可以被认为类似于人类的代谢综合征，但目前还不清楚是什么潜在的机制决定了这些变化，以及是否涉及更广泛的特征。要确定该系统作为人类疾病模型的实用性，将需要更深入的研究，但如果这些鱼也进化到减轻这些特征的负面影响，则可能特别有价值。因此，我们的目标是确定这些鱼的身体组成是如何使用一种综合的方法，占遗传，表观遗传和环境线索。这种方法应该更紧密地匹配性状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和周围种群的棘鱼之间的代谢差异，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肝的迹象，并测试血液中甘油三酯和胆固醇的浓度是否发生在地热鱼中（预计这将发生在身体脂肪水平较高的情况下）。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，它可以为人类提供进一步的见解甚至治疗方法。