Fasteen Tess D, Hernandez Melody R, Policastro Robert A, Sterrett Maria C, Zenter Gabriel E, Tennessen Jason M
Department of Biology, Indiana University, Bloomington, IN.
J Lipid Res. 2025 Apr 25;66(6):100815. doi: 10.1016/j.jlr.2025.100815.
The estrogen-related receptor (ERR) family of nuclear receptors serves key roles in coordinating triglyceride (TAG) accumulation with juvenile growth and development. In both insects and mammals, ERR activity promotes TAG storage during the postembryonic growth phase, with loss-of-function mutations in mouse Esrra and Drosophila melanogaster dERR inducing a lean phenotype. However, the role of insect ERRs in controlling TAG accumulation within adipose tissue remains poorly understood, as nearly all transcriptomic and metabolomic studies have relied on whole animal analyses. Here, we address this shortcoming by using tissue-specific approaches to examine the role of dERR in regulating lipid metabolism within the Drosophila larval fat body. We find that dERR autonomously promotes TAG accumulation within fat body cells and regulates expression of genes involved in glycolysis, β-oxidation, and isoprenoid metabolism. As an extension of these results, we not only discovered that dERR mutant fat bodies exhibit decreased expression of known dHNF4 target genes but also found that dHNF4 activity is decreased in dERR mutants. Overall, our findings indicate that dERR plays a multifaceted role in the larval fat body to coordinate lipid storage with carbohydrate metabolism and developmental growth.
核受体雌激素相关受体（ERR）家族在协调甘油三酯（TAG）积累与幼年生长发育过程中发挥着关键作用。在昆虫和哺乳动物中，ERR活性在胚胎后生长阶段促进TAG储存，小鼠Esrra和果蝇dERR的功能丧失突变会导致瘦型表型。然而，由于几乎所有的转录组学和代谢组学研究都依赖于对整个动物的分析，昆虫ERRs在控制脂肪组织内TAG积累方面的作用仍知之甚少。在这里，我们通过使用组织特异性方法来研究dERR在调节果蝇幼虫脂肪体脂质代谢中的作用，从而解决这一缺陷。我们发现dERR自主促进脂肪体细胞内的TAG积累，并调节参与糖酵解、β-氧化和类异戊二烯代谢的基因表达。作为这些结果的延伸，我们不仅发现dERR突变体脂肪体中已知的dHNF4靶基因表达降低，还发现dERR突变体中dHNF4活性降低。总体而言，我们的研究结果表明，dERR在幼虫脂肪体中发挥多方面作用，以协调脂质储存与碳水化合物代谢及发育生长。
