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一种用于测量果蝇胰岛素信号转导调节和生理学的遗传策略。

A genetic strategy to measure insulin signaling regulation and physiology in Drosophila.

机构信息

Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.

Department of Medicine (Division of Endocrinology, Metabolism, Gerontology), Stanford University School of Medicine, Stanford, California, United States of America.

出版信息

PLoS Genet. 2023 Feb 2;19(2):e1010619. doi: 10.1371/journal.pgen.1010619. eCollection 2023 Feb.

DOI:10.1371/journal.pgen.1010619
PMID:36730473
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9928101/
Abstract

Insulin regulation is a hallmark of health, and impaired insulin signaling promotes metabolic diseases like diabetes mellitus. However, current assays for measuring insulin signaling in all animals remain semi-quantitative and lack the sensitivity, tissue-specificity or temporal resolution needed to quantify in vivo physiological signaling dynamics. Insulin signal transduction is remarkably conserved across metazoans, including insulin-dependent phosphorylation and regulation of Akt/Protein kinase B. Here, we generated transgenic fruit flies permitting tissue-specific expression of an immunoepitope-labelled Akt (AktHF). We developed enzyme-linked immunosorption assays (ELISA) to quantify picomolar levels of phosphorylated (pAktHF) and total AktHF in single flies, revealing dynamic tissue-specific physiological regulation of pAktHF in response to fasting and re-feeding, exogenous insulin, or targeted genetic suppression of established insulin signaling regulators. Genetic screening revealed Pp1-87B as an unrecognized regulator of Akt and insulin signaling. Tools and concepts here provide opportunities to discover tissue-specific regulators of in vivo insulin signaling responses.

摘要

胰岛素调节是健康的标志，而胰岛素信号转导受损会促进糖尿病等代谢疾病。然而，目前用于测量所有动物胰岛素信号转导的方法仍然是半定量的，缺乏敏感性、组织特异性或时间分辨率，无法定量体内生理信号转导动力学。胰岛素信号转导在包括依赖胰岛素的磷酸化和 Akt/蛋白激酶 B 调节在内的后生动物中非常保守。在这里，我们生成了转基因果蝇，允许免疫表位标记的 Akt (AktHF)在组织中特异性表达。我们开发了酶联免疫吸附测定 (ELISA) 来定量单个果蝇中磷酸化 (pAktHF) 和总 AktHF 的皮摩尔水平，揭示了 pAktHF 在响应禁食和再喂养、外源性胰岛素或靶向遗传抑制已建立的胰岛素信号转导调节剂时的动态组织特异性生理调节。遗传筛选显示 Pp1-87B 是 Akt 和胰岛素信号转导的未被识别的调节剂。这里的工具和概念为发现体内胰岛素信号转导反应的组织特异性调节剂提供了机会。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/a9ccdd1e5819/pgen.1010619.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/9d51e45b261e/pgen.1010619.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/cb7fa22f4167/pgen.1010619.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/c133b2bcd933/pgen.1010619.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/2ef9dd2b542d/pgen.1010619.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/ff8220825082/pgen.1010619.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/a9ccdd1e5819/pgen.1010619.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/9d51e45b261e/pgen.1010619.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/cb7fa22f4167/pgen.1010619.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/c133b2bcd933/pgen.1010619.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/2ef9dd2b542d/pgen.1010619.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/ff8220825082/pgen.1010619.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4760/9928101/a9ccdd1e5819/pgen.1010619.g006.jpg

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