Department of Biological Sciences, Purdue University Fort Wayne, Fort Wayne, IN, United States of America.
PLoS One. 2024 Aug 28;19(8):e0302565. doi: 10.1371/journal.pone.0302565. eCollection 2024.
Obesity is a growing concern. 42.3% of people in the U.S were considered obese between 2017-2018. Much is still unknown about the genetic components that contribute to weight gain. In humans, the hormone glucagon is a major contributor to the body's energy regulation as it signals for the breakdown of lipids. Treatments targeting the glucagon pathway have helped patients with both weight loss and appetite suppression. Understanding the genetic modifiers of glucagon signaling and its downstream pathways could enable the development of a wider variety of effective therapeutics. In this study, we blocked the glucagon pathway in Drosophila melanogaster by reducing the expression of the fly ortholog of the glucagon receptor (AKHR). We then crossed our model to the Drosophila Genetic Reference Panel (DGRP) and looked for natural variation in fat content. We used variation in larval density to identify candidate modifier genes through a genome-wide association study. We then tested these modifier genes by increasing or decreasing their expression in the AKHR model. We screened these candidates initially with the same density assay used in the original study to narrow down to four candidate genes that substantially impacted the density of the larvae: THADA, AmyD, GluRIIC, and CG9826. We further characterized these candidates using biochemical assays to analyze stored metabolites such as triglycerides, glucose, glycogen, and protein under control, high sugar, and high fat conditions to see if the larvae are resistant to environmental changes. Our results indicate consistency between the results of the density assay and direct measurement of metabolite levels. In particular, THADA and AmyD are highlighted as interesting genes for additional study. We hope to improve our understanding of the glucagon signaling pathway, obesity, and lipid metabolism. We also aim to provide candidate genes that can be regarded as future therapeutic targets.
肥胖是一个日益严重的问题。在 2017-2018 年期间，美国有 42.3%的人被认为患有肥胖症。关于导致体重增加的遗传因素，我们还有很多未知之处。在人类中，激素胰高血糖素是身体能量调节的主要贡献者，因为它会发出信号，促进脂质分解。针对胰高血糖素途径的治疗方法已经帮助患者减轻体重和抑制食欲。了解胰高血糖素信号及其下游途径的遗传修饰因子可能会开发出更广泛的有效治疗方法。在这项研究中，我们通过降低果蝇胰高血糖素受体（AKHR）的同源物的表达来阻断果蝇黑素体中的胰高血糖素途径。然后，我们将我们的模型与果蝇遗传参考面板（DGRP）交叉，并寻找脂肪含量的自然变异。我们使用幼虫密度的变化通过全基因组关联研究来鉴定候选修饰基因。然后，我们通过增加或减少 AKHR 模型中的这些修饰基因的表达来测试这些候选基因。我们最初使用原始研究中使用的相同密度测定法筛选这些候选基因，以将候选基因缩小到四个对幼虫密度有重大影响的候选基因：THADA、AmyD、GluRIIC 和 CG9826。我们使用生化测定法进一步对这些候选基因进行了表征，以分析在对照、高糖和高脂肪条件下储存的代谢物，如甘油三酯、葡萄糖、糖原和蛋白质，以确定幼虫是否对环境变化有抵抗力。我们的结果表明，密度测定法的结果与代谢物水平的直接测量之间具有一致性。特别是，THADA 和 AmyD 被突出为进一步研究的有趣基因。我们希望提高对胰高血糖素信号通路、肥胖和脂质代谢的理解。我们还旨在提供可被视为未来治疗靶点的候选基因。
