Comparative transcriptomics of lateral hypothalamic cell types reveals conserved growth hormone-tachykinin dynamics in feeding

Comparative transcriptomics of lateral hypothalamic cell types reveals conserved growth hormone-tachykinin dynamics in feeding

Molecular Metabolism

10.1016/j.molmet.2025.102251

https://doi.org/10.1016/j.molmet.2025.102251

Vindhya Chaganty, Ruey-Kuang Cheng, Kimberle Shen, Na Zhang, Gaynah Javier Doblado, Sarah Ong, Sandra Tan, Valarie Yu Yan Tham, Jung-Hwa Choi, Marnie E. Halpern, Wei Leong Chew, Anand Kumar Andiappan, Sarah Xinwei Luo, Caroline Lei Wee

Zebrafish., Comparative transcriptomics, Lateral hypothalamus, Appetite regulation, Growth hormone

13 September 2025

Chaganty, V., Cheng, R.-K., Shen, K., Zhang, N., Doblado, G. J., Ong, S., Tan, S., Tham, V. Y. Y., Choi, J.-H., Halpern, M. E., Chew, W. L., Andiappan, A. K., Luo, S. X., & Wee, C. L. (2025). Comparative transcriptomics of lateral hypothalamic cell types reveals conserved growth hormone-tachykinin dynamics in feeding. Molecular Metabolism, 102, 102251. https://doi.org/10.1016/j.molmet.2025.102251

Objectives The lateral hypothalamus (LH) plays a central role in appetite control, however the functional and evolutionary conservation of its subcircuits remain unclear. This study aimed to define the molecular and cellular identities of zebrafish LH neurons, identify conserved LH cell types across vertebrates, and investigate their roles in appetite regulation. Methods We performed the Act-seq method of single-cell RNA sequencing in the larval zebrafish LH under food-deprived and voracious feeding states to capture activity-dependent transcriptional signatures. Using integrative comparative transcriptomics, we aligned zebrafish neuronal clusters with a published mouse LH dataset to identify conserved neuronal sub-populations, and performed functional and molecular characterisation of a highly-conserved cell type in both zebrafish and mice. Results We identified several LH neuronal subtypes in zebrafish that are differentially activated during voracious feeding. Cross-species mapping revealed overlapping cellular clusters, especially for GABAergic neurons. We report a conserved GABAergic cluster co-expressing growth hormone (GH) receptors and tachykinin. In both species, feeding activates these neurons and elevates GH receptor and tachykinin expression. In zebrafish, upstream GH signaling is similarly regulated by feeding state, and acute GH administration both activates this cluster and enhances food intake. Conclusions These findings uncover a conserved GH receptor-tachykinin LH population which may link metabolic hormone signaling to appetite control. Beyond its established long-term roles in growth and metabolism, we propose that GH exerts acute appetite-enhancing effects through activation of this neuronal pathway. Our comparative LH atlas highlights the evolutionary biology of hypothalamic appetite circuits.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This research / project is supported by the National Research Foundation - National Research Foundation Fellowship
Grant Reference no. : NRF-NRFF13-2021-0003

This research / project is supported by the Agency for Science, Technology and Research (A∗STAR) - Agency for Science, Technology and Research (A∗STAR) Strategic Research Program Brain-Body Initiative
Grant Reference no. : iGrants call ID: #21718

This research / project is supported by the Singapore Food Agency - Singapore Food Story R&D programme
Grant Reference no. : W22W3D0003

This research / project is supported by the National Medical Research Council - National Medical Research Council Open Fund - Young Individual Research Grant (OF-YIRG)
Grant Reference no. : SC18/24-727015

This research is supported by core funding from: Institute of Molecular and Cell Biology
Grant Reference no. :

© 2025 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

https://oar.a-star.edu.sg/communities-collections/articles/22346

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Institute of Molecular and Cell Biology

https://doi.org/10.1016/j.molmet.2025.102251