Hormonal
Human hypothalamic melanocortin neurons (POMC and AgRP) exhibit significant transcriptomic and receptor-expression differences compared to mice, including species-specific GPCR profiles that directly impact the mechanism and efficacy of current obesity therapies.
Current obesity treatments like semaglutide and tirzepatide target the hypothalamus, but their exact molecular mechanisms in humans may differ from what we learned from mouse studies. This map reveals that human POMC neurons express different receptors (like CALCR) than mouse POMC neurons. This means drug developers must account for these human-specific differences to improve efficacy and reduce side effects, rather than relying solely on rodent data.
Specifically, there are significant disparities in the identity of pro-opiomelanocortin neurons and in the expression levels of G-protein-coupled receptors between the two species that carry direct implications for currently approved obesity treatments.
Why this rating
Based on a comprehensive single-nucleus sequencing and spatial transcriptomics atlas of 433,369 human cells, providing high-resolution molecular data.
Source
A comprehensive spatio-cellular map of the human hypothalamus
John A. Tadross et al. · Nature · 2025
DOI 10.1038/s41586-024-08504-8
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