Drosophila Kruppel homolog 1 represses lipolysis through interactions with dFOXO

Authors: KANG, PING - Iowa State University; CHANG, KAI - Iowa State University; LIU, YING - Iowa State University; BOUSKA, MARK - Iowa State University; KARASHCHUK, GALENA - Brown University; THAKORE, RACHEL - Brown University; WANG, WENJING - Brown University; POST, STEPHANIE - Brown University; Brent, Colin; LI, SHENG - Chinese Academy Of Sciences; TATAR, MARC - Brown University; BAI, HUA - Brown University

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/15/2017
Publication Date: 11/27/2017
Citation: Kang, P., Chang, K., Liu, Y., Bouska, M., Karashchuk, G., Thakore, R., Wang, W., Post, S., Brent, C.S., Li, S., Tatar, M., Bai, H. 2017. Drosophila Kruppel homolog 1 represses lipolysis through interactions with dFOXO. Scientific Reports. 7:16369.

Interpretive Summary: Coordination of gene expression is a vital process contributing to metabolic homeostasis. As one of the key nodes in the metabolic network, the forkhead transcription factor FOXO has been shown to interact with diverse transcription co-factors and integrate signals from multiple pathways to control metabolism, oxidative stress responses and the cell cycle. Recently, insulin/FOXO signaling has been implicated in the regulation of insect development via the interaction with insect hormones, such as ecdysone and juvenile hormone. However, the underlying mechanisms of these interactions remains largely unclear. In this study, we identified an interaction effect between dFOXO and the zinc finger transcription factor Kruppel homolog 1 (Kr-h1), one of the key players in juvenile hormone signaling. We found that kr-h1 mutants of Drosophila melanogaster have a reduced capacity to store fats and handle process sugars, and exhibit delayed larval development. Notably, Kr-h1 interacts with dFOXO to regulate the expression of genes for insulin receptors and fat enzyme, as well as the duration of the pupal stage. The co-regulation of these factors by Kr-h1 and dFOXO could provide insights into the molecular basis of the cross-talk between the juvenile hormone and insulin signaling pathways during insect development.

Technical Abstract: Juvenile hormone (JH) is a key endocrine signal involved in insect molting and metamorphosis. Recent studies suggest that JH is involved in not only development programming, but also in metabolic control. However, how JH modulates metabolism remains largely unknown. It has been shown that JH induces the expression of kruppel-like factor kr-h1 transcriptional activity via the JH receptor Methoprene-tolerant (Met). Here, we identified transcriptional co-regulation of insulin signaling and lipolysis through the interaction between Kr-h1 and dFOXO, a forkhead transcription factor downstream of insulin/insulin-like growth factor signaling. In fasting Drosophila melanogaster larvae, Kr-h1 co-localizes with dFOXO in nuclei of fat body cells. Through its transaction/repressor domain Kr-h1 physically binds to dFOXO and negatively regulates dFOXO target genes, including insulin receptor (InR) and adipose TAG lipase brummer (bmm). Accordingly, Kr-h1 genetically interacts with dFOXO to control pupariation timing and lipid metabolism. We also showed that JH signaling, an upstream regulator of Kr-h1, regulates the transcription of brummer lipase though dFOXO. Transcriptome analysis reveals that Kr-h1 targets many metabolic genes that overlap with dFOXO targets. Thus, the interaction between Kr-h1 and dFOXO may represent a broad mechanism by which metabolic signaling integrates with JH-regulated developmental programs to coordinate organism growth.