Drosophila pyruvate kinase links metabolic state with circadian output via TARANIS and PDF

The circadian clock generates ~24-hour rhythms that allow organisms to anticipate daily environmental fluctuations. The clock and glucose metabolism are tightly interconnected, and their disruption commonly co-occurs in aging and disease, yet how glucose hypometabolism impacts circadian rhythm remains unclear. Here, we downregulated key glycolytic enzymes - Hexokinase-C, Phosphofructokinase, and Pyruvate kinase (Pyk) - in Drosophila clock cells.

Only Hexokinase-C and Pyk knockdown altered circadian period, lengthening and shortening it respectively, consistent with their mRNA reduction. Pyk knockdown induced period shortening persisted in adult-specific KD (AKD), minimizing developmental confounds, and reduced both PERIOD and Pigment-dispersing factor (PDF) levels. We identified the transcriptional coregulator TARANIS (TARA), as a crucial mediator.

Pyk AKD lowered tara mRNA and protein, whereas tara overexpression rescued the short-period phenotype and PDF levels. Our findings establish a PYK-TARA-PDF axis linking glycolytic activity to circadian neuropeptide output, offering insight into metabolic contributions to circadian disruption in aging and neurodegeneration. We are very grateful to Jongkyeong Chung (Seoul National University, Republic of Korea) for providing UAS-Pyk-HA flies and Paul E.

Hardin (Texas A&M University, USA) for providing anti-VRI antibodies. We also thank the members of the KEY laboratory for their insightful discussions and comments. Drosophila stocks were obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) and Vienna Drosophila Resource Center (VDRC, www.vdrc.at). were used in this study.

This research was supported by grants from the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT to Sang Hyuk Lee (M-2024-A0403-00020), to Eun Young Kim (RS-2023-00208490, RS-2025-24534961, RS-2026-25485901, and RS-2026-25519531) as well as the National Institutes of Health of USA to Kyunghee Koh (R01NS086887). Department of Brain Science, Ajou University School of Medicine, Suwon, Republic of Korea Sang Hyuk Lee, So Who Kang, Eunjoo Cho, Ji Min Ahn & Eun Young Kim Department of Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea Sang Hyuk Lee, So Who Kang, Ji Min Ahn & Eun Young Kim Department of Psychiatry, Ajou University School of Medicine, Suwon, Republic of Korea Department of Neuroscience, The Farber Institute for Neurosciences and Synaptic Biology Center, Thomas Jefferson University, Philadelphia, PA, USA BK21 R&E Initiative for Advanced Precision Medicine, Graduate School of Ajou University, Suwon, Republic of Korea Department of Pharmacology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea Correspondence to Kyunghee Koh or Eun Young Kim. The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.